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Diabetic nephropathy (DN) is one of the most severe diabetic complications, which can easily progress into irreversible and detrimental end-stage renal disease if not properly controlled. However, the effective prevention of DN progression has always remained a huge challenge. Moderate intensity static magnetic fields (SMFs), which have the advantages of non-invasive and high penetration, have shown beneficial effects in reducing blood glucose in type 2 diabetes mice in recent years. In this study, by using both db/db severe diabetic mice and high-fat diet and streptozotocin-induced moderate diabetic mice, we found that SMFs have significant effects on reducing DN compared to blood glucose control. Further analyzing the db/db mice with severe diabetes, we found that kidney inflammation, vascular abnormalities, and fibrosis were all greatly reduced. Moreover, SMFs can promote macrophages polarized into M2. In vitro cellular experiments also demonstrate the positive effects of SMFs in reducing kidney cell inflammation, as well as increasing M2 macrophage polarization by promoting F-actin assembly. Therefore, our results show that moderate intensity SMFs have great potential to be developed as a new physical modality to be used in the treatment of DN, and possibly other types of chronic kidney diseases., (© 2025 Federation of American Societies for Experimental Biology.)

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide, and podocyte ferroptosis plays a crucial role in its pathogenesis. Hirsutine (HS) reduces blood glucose levels and improve insulin resistance in diabetic mice, suggesting its potential use in diabetes treatment. Here, we established a db/db mouse model of DKD and administered HS for 8 weeks. We found that HS decreased the concentrations of iron, reactive oxygen species (ROS), and malondialdehyde (MDA) in renal tissues. Furthermore, HS treatment restored mitochondrial morphology, increased Glutathione Peroxidase 4(GPX4) levels, and decreased p53 levels, alleviating podocyte loss in the DKD mouse model. However, the effects of HS were reversed by the p53 activator Nutlin-3. Therefore, we propose HS may mitigate podocyte injury in DKD by regulating the p53/GPX4 pathway, providing a novel strategy for targeting podocyte ferroptosis in DKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Diabetic kidney disease (DKD) is one of the common and serious complications of type 2 diabetes mellitus (T2DM). Metformin is commonly prescribed for the treatment of T2DM, while exercise is frequently recommended as adjunctive therapy. However, the therapeutic efficacy and molecular etiology of combined therapy with exercise and metformin in DKD remain to be elucidated. The present study therefore aimed to investigate the therapeutic effects and mechanisms underlying the combined effects of exercise and metformin on DKD. A rat model of T2DM was constructed by administering a high-fat diet and intraperitoneal injections of streptozotocin (30 mg/kg) for 6 weeks. The rats with T2DM exhibited reduced autophagic flux, increased oxidative stress, and morphological and structural lesions in the kidneys, compared to those of normal rats in the control group. The combination of exercise and metformin alleviated DKD, indicated by the elevation of renal autophagic flux, and a reduction in oxidative stress, renal fibrosis, and histopathological damage to the kidneys. Our findings suggested that exercise combined with metformin has a therapeutic role in DKD, and the study serves as a valuable reference for future research on the treatment of DKD., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests with regard to the publication of this article., (Copyright © 2025. Published by Elsevier Inc.)

Diabetic kidney disease (DKD), a common diabetes complication, often progresses to end-stage renal disease (ESRD) Lipid accumulation is crucial in DKD progression, and its dysregulation causes ectopic fat distribution, inflammation, and renal damage. Soyasapogenol C (SSC) has various therapeutic potentials. However, its effect on DKD and the underlying mechanisms are unknown. This study explores SSC's role in improving DKD, especially in db/db mice, an ideal DKD research model. We hypothesize that by modulating lipid metabolism, especially cholesterol metabolism, SSC could treat DKD. Results show SSC inhibits cholesterol accumulation, interstitial fibrosis, and renal inflammation in db/db mice. In vitro, it suppresses cholesterol accumulation in HK2 cells and increases ABCA1 and ABCG1 levels. Mechanistically, SSC upregulates ABCA1 and ABCG1 via liver X receptor α (LXRα), and this is inhibited by LXRα inhibitor or siRNA knockdown. Our findings offer new insights into SSC's role in cholesterol metabolism and lipid deposition, and new DKD treatment targets., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Objective: Epimedium glycoside is a flavonoid compound in Epimedium, which has been found to alleviate various chronic diseases. The effect and mechanism of icariin on the treatment of diabetes nephropathy still need to be clarified. In this study, we conducted network pharmacology and molecular docking analysis to reveal the mechanism of icariin treating DKD, and then validated its efficacy using a cell model., Method: The structure and targets of icariin were screened using Traditional Chinese Medicine Systems Pharmacology (TCMSP), and their targets were annotated. Retrieve DKD targets from OMIM, GeneCards, and TTD databases. We constructed a protein-protein interaction (PPI) network using the STRING platform and visualized the results using Cytoscape 3.9.1 software. We also conducted GO and KEGG enrichment analysis on icariin and then performed molecular docking between icariin and key targets. Finally, we established a cell model of DKD to evaluate the efficacy of icariin in treating DKD., Result: A total of 77 icariin targets were associated with DKD. The GO and KEGG enrichment results showed that the therapeutic effect of icariin on DKD was significantly correlated with inflammatory response, cell apoptosis, epithelial-mesenchymal transition, and PI3K/AKT signaling pathway. The molecular docking results indicate that icariin has a high affinity for key targets EGER, AKT1, and IGF1. Cell experiments showed that icariin inhibited high glucose-induced EMT, fibrosis-related proteins, levels of inflammatory factors TGF-β1, IL-6, and TNF-α, as well as phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in renal tubular epithelial cells. In addition, icariin inhibited the increase in EGER and AKT1 mRNA levels caused by high glucose and alleviated the decrease in IGF1 mRNA levels., Conclusion: Epimedium glycoside may protect DKD by targeting EGER, AKT1, and IGF1 to inhibit PI3K/AKT signaling, but the specific mechanism needs further exploration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: Diabetic nephropathy (DN) is a primary microvascular complication of diabetes with characteristics of renal fibrosis. Seabuckthorn polysaccharide (SP) is an extract from Seabuckthron berries (Hippophae rhamnoides L.) with antioxidant, anti-fatigue, anti-inflammation, and hepatoprotective properties. This current work aimed to investigate the effect of SP on DN-induced kidney fibrosis., Methods: STZ-induced DN mouse model was constructed by intraperitoneally injecting 50 mg/kg STZ for five days. Various doses of SP were orally administered to mice. Biochemical analysis was performed to measure blood biochemical parameters. Masson's trichrome staining of renal tissues was conducted to analyze fibrotic area. Immunofluorescence staining was performed to assess E-cadherin and α-SMA expressions in kidney samples. Serum MMP2 level was evaluated by corresponding ELISA kit, and Timp2 level was subjected to RT-qPCR analysis. PCR and western blot were conducted to quantify p311, TGFβ1, and Fstl1 levels in renal samples., Results: SP reversed the changes in body weight, fasting blood glucose and renal function indicators in diabetic mice. SP lessened renal fibrotic areas in diabetic mice and inhibited epithelial-mesenchymal transition (EMT) by increasing E-cadherin level and reducing α-SMA expression. Fibrotic genes MMP2 and TIMP2 were highly expressed in mice with DN, and their dysregulated expressions were reversed by SP administration. Additionally, SP suppressed the activation of p311/TGFβ1/Fstl1 signaling pathway in renal tissues of diabetic mice., Conclusions: SP alleviates diabetic nephropathy by improving renal functions, alleviating renal fibrosis, and hampering EMT process via downregulation of fibrotic genes and inactivation of the p311/TGFβ1/Fstl1 pathway., Competing Interests: Declaration of Competing Interest None., (Copyright © 2025 Elsevier GmbH. All rights reserved.)

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and effective treatment modalities that fully address its molecular etiology are lacking. Prior studies support that the stress response protein REDD1 (regulated in development and DNA damage 1) contributes to the development of diabetes complications. This study investigated a potential role for REDD1 expression in podocytes in diabetes-induced podocyte loss and compromised glomerular filtration. Podocyte-specific REDD1 deletion protected against renal injury, as evidenced by reduced albuminuria, glomerular hypertrophy, and mesangial matrix deposition in streptozotocin (STZ)-induced diabetic mice. Podocyte-specific REDD1 expression was required for diabetes-induced reduction in slit diaphragm (SD) proteins podocin and nephrin. Notably, podocyte-specific REDD1 deletion protected against podocytopenia and preserved glomerular basement membrane and foot process architecture in diabetic mice. In the kidneys of diabetic mice and in human podocyte cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the transient receptor potential canonical 6 (TRPC6) channel. More specifically, REDD1 promoted nuclear factor-κB-dependent transcription of TRPC6, intracellular calcium entry, and cytoskeletal remodeling under hyperglycemic conditions. Overall, the findings provide new insight into the role of podocyte-specific REDD1 expression in renal pathology and support the possibility that therapeutics targeting REDD1 in podocytes could be beneficial for DN., Article Highlights: Diabetes-induced albuminuria and reduced glomerular slit diaphragm proteins were associated with increased kidney REDD1 protein abundance. Podocyte-specific deletion of REDD1 attenuated diabetes-induced slit diaphragm protein reduction and podocyte loss. REDD1 was required for nuclear factor-κB-dependent TRPC6 expression and increased cytoplasmic calcium levels in podocytes. Podocyte-specific expression of REDD1 was necessary for altered glomerular architecture and albuminuria in diabetic mice., (© 2024 by the American Diabetes Association.)

Podocyte injury plays a pivotal role in the pathogenesis of diabetic nephropathy (DN), leading to proteinuria formation. β-Sitosterol is a natural compound with anti-inflammatory, anti-diabetic, nephroprotective and antioxidant properties. The studyaimed to explore whether and how β-Sitosterol protected podocytes against high glucose (HG)-induced inflammatory andoxidative injury. DN cell models were established by stimulating podocytes or renal tubular epithelial cells (HK-2) cells with 25 mM glucose. Cell viability and apoptosis were evaluated using cell counting kit-8 assays and flow cytometry analyses. Westernblotting was used to quantify protein levels of genes related to podocyte injury, HK-2 cell damage, inflammation, and TLR4/NF-кB pathway. Contents of oxidative stress biomarkers were evaluated by corresponding commercial kits while proinflammatorycytokine levels were determined by enzyme-linked immunosorbent assay. Immunofluorescence staining was performed todetect intracellular levels of reactive oxygen species (ROS) and Nrf2 nuclear translocation. Experimental results revealed that HG treatment induced podocyte dysfunction by impairing cell viability while accelerating theapoptosis, and the changes were reversed by β-sitosterol treatment. Moreover, β-sitosterol repressed HG-evoked oxidative stressby reducing ROS and malondialdehyde (MDA) levels while increasing activities of antioxidant enzymes. The reduction ofproinflammatory cytokines mediated by β-sitosterol in HG-stimulated podocytes suggested the anti-inflammatory role of β-sitosterol. Additionally, the activation of the TLR4/NF-кB signaling induced by HG was inhibited by β-sitosterol in podocytes.Inactivation of the TLR4 using TAK-242 enhanced the protective effects of β-sitosterol against HG-mediated oxidative stressand inflammation. Similarly, β-sitosterol also protected HK-2 cells from HG-induced oxidative stress, inflammation, andapoptosis. In summary, β-sitosterol exerts anti-inflammatory, anti-oxidative, and anti-apoptotic activities in HG-induced podocytes or HK-2 cells by inhibiting TLR4/NF-кB signaling., Competing Interests: Compliance with Ethical Standards. Conflict of Interest: The authors declare no competing interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The etiology of diabetic kidney disease (DKD) is multifaceted, with hyperglycemia, inflammation, oxidative stress, and fibrosis recognized as key contributors to renal damage in individuals with DKD. Clinical evidence suggests that dapagliflozin not only reduces blood glucose levels but also demonstrates superior efficacy in ameliorating pancreatic islet cell injury while preserving cardiac and renal function. However, the precise underlying mechanism has been poorly elucidated in the current literature. In this study, a DKD rat model was established by administering a single intraperitoneal injection of streptozotocin (STZ) to investigate the renoprotective properties of dapagliflozin and its underlying mechanisms. The findings of this study indicate that dapagliflozin enhanced pancreatic islet cell function, lowered blood glucose levels, and significantly reduced biochemical markers and renal pathological damage in DKD rats. Dapagliflozin also exerted anti-inflammatory, antioxidant, and antifibrotic effects by inhibiting the activation of the p38 MAPK/NF-κB pathway, enhancing the activity of the SIRT1/Akt/GSK-3β/Nrf2/HO-1 signaling pathway, and inhibiting the over-activation of the TGF-β1/Smad2/3 signaling pathway. These effects led to a reduction in renal injury and improved renal function in DKD rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84%) and Type 1 diabetes (16%), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyses in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Diabetic kidney disease (DKD), a microvascular complication of diabetes mellitus, represents a significant clinical challenge. This study investigated the reno-protective effects of dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) widely used in the management of diabetes, and aimed to elucidate its underlying mechanisms. Mice with db/db and db/m genotypes were allocated into four experimental groups and treated with either dulaglutide or a saline control for 10 weeks. Following the treatment period, biological samples were collected for comprehensive analysis. Serum and urinary creatinine levels were measured using a creatinine assay, while urinary protein concentrations were quantified via ELISA. Histopathological kidney damage was assessed through hematoxylin and eosin (HE) staining, with glomerular lesions evaluated using periodic acid-Schiff (PAS) staining. Inflammatory markers, ferroptosis-related indicators, and fibrosis in kidney tissues were further analyzed through PCR, Western blot (WB), immunohistochemistry (IHC), and transmission electron microscopy (TEM). Consistent with prior findings, this research demonstrated that dulaglutide improves renal function and mitigates pathological kidney damage in db/db mice. Treatment with dulaglutide significantly reduced mRNA expression of ferroptosis-related markers, including ACSL4, SLC7A11, and Ptgs2, alongside a decrease in 4-HNE levels in kidney tissues. Furthermore, dulaglutide downregulated ACSL4 protein levels and upregulated GPX4 protein expression, thereby ameliorating mitochondrial damage in renal tubular cells. In addition to these effects, dulaglutide alleviated kidney inflammation and fibrosis in db/db mice, with concomitant suppression of P-STAT3 and P-ERK expression. Collectively, these findings underscore dulaglutide's reno-protective effects in DKD, mediated through the inhibition of inflammation, improvement in renal fibrosis and ferroptosis, and modulation of P-STAT3 and P-ERK signaling pathways., Competing Interests: Declaration of competing interest The authors disclose that no known financial interests or personal relationships exist that might have appeared to affect the work documented in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

The role of ER stress in the pathogenesis of diabetic kidney diseases (DKD) remains unclear. We employed bioinformatics to identify the UPR pathway activation, inflammation, and programmed cell death patterns in diabetic tubules. Levels of IRE1α/sXBP1 signaling, NLRP3 inflammasome activity and pyroptosis in tubular cells under high glucose conditions were measured. IRE1α knockdown was used to determine its role in glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. PDIA4 overexpression and silencing were used to assess its impact on the IRE1α/sXBP1 pathway. The dynamic interaction among PDIA4, GRP78, and IRE1α under high glucose were analyzed using immunoprecipitation and crosslinking assays. In STZ-induced and db/db mouse models of DKD, the regulatory role of PDIA4 on IRE1α/sXBP1 signaling and diabetic tubular inflammation and injury were evaluated. Our study showed that IRE1α/sXBP1, NLRP3 inflammasome, and pyroptosis are activated in the renal tubules of DKD patients. Induction of IRE1α pathway mediated the glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. Moreover, overexpression of PDIA4 decreased the activation of IRE1α/sXBP1 under high glucose conditions. High glucose leads to the release of GRP78 from IRE1α and an increased interaction between IRE1α and PDIA4. In mouse models of DKD, overexpressing PDIA4 mitigated diabetic tubular injury and inflammation, marked by decreased IRE1α/sXBP1 and NLRP3 inflammasome. In conclusion, our findings demonstrate that high glucose triggers NLRP3 inflammasome and pyroptosis via the IRE1α/sXBP1 pathway in renal tubular cells. Overexpression of PDIA4 suppresses IRE1α signaling by binding to its oligomeric form, implying a promising therapeutic intervention for DKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Both type 1 and type 2 diabetes can lead to diabetic nephropathy (DN), a serious microvascular complication. Bromodomain 4 (BRD4), a member of the BET protein family, has been linked to various diseases, including cancer, inflammation, and fibrosis, and may be involved in the development of diabetes and its complications. In this study, we first explored the role and mechanism of BRD4 in DN. We found that BRD4 expression was upregulated in both diabetic cells and animal models, and that BRD4 knockdown alleviated DN. Therefore, we next investigated the effect of AT1, a small-molecule degrader of BRD4 based on proteolysis targeting chimera (PROTAC) technology, on DN improvement. PROTAC has seldom been applied to non-oncological diseases, and this study represents the first application of AT1 to DN. Finally, we explored the molecular mechanisms underlying DN improvement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Diabetic kidney disease 2 (DKD) is a chronic complication of diabetes characterized by kidney damage due to persistent hyperglycemia. A growing number of evidence indicated that circular RNAs 3 (circRNAs) play a crucial role in diabetes and associated complications. However, the function and mechanism of circRNAs in DKD remain unclear. Herein, we investigated the expression profiles of circRNAs in DKD mice compared to non-diabetic mice using RNA-seq analysis. A novel circRNA, circMRP4, derived from the circularization of Multidrug resistance-associated protein 4 4 (MRP4) was identified. The expression of circMRP4 was significantly increased in both kidney tissues of DKD and mouse podocytes exposed to high glucose 5 (HG). In addition, knockdown of circMRP4 alleviated podocytes apoptosis and inflammation induced by HG, while circMRP4 overexpression resulted in the opposite impact. Dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assay demonstrated that circMRP4 could directly target miR-499-5p which was closely associated with podocytes apoptosis and inflammation. Furthermore, circMRP4 was found to act as a sponge for miR-499-5p, leading to the upregulation of its target RRAGB, thereby activating the mTORC1/P70S6K signaling. In summary, our findings suggested that circMRP4 mediated podocytes apoptosis and inflammation in DKD by modulating the miR-499-5p/RRAGB/mTORC1/P70S6K axis, highlighting circMRP4 as a potential therapeutic target for DKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-α secretion causing podocyte apoptosis. The AH-induced monocyte TNF-α secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-α release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-α secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-α release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel anti-inflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes., Competing Interests: Declaration of Competing Interest Authors have no conflicts to declare., (Published by Elsevier Ltd.)

Diabetic nephropathy (DN) is a common complication of diabetes and a major cause of end-stage renal disease, with complex pathogenesis involving inflammation, oxidative stress, fibrosis, and ferroptosis. Ferroptosis is linked to DN progression, yet treatment options are limited, particularly for targeting ferroptosis. Dapagliflozin (DAPA), an SGLT2 inhibitor, shows renal protective effects in diabetes, but its role in renal fibrosis and ferroptosis in DN is unclear. This study investigated DAPA's effect on renal fibrosis in DN by inhibiting ferroptosis, using a streptozotocin-induced diabetic mouse model. Results indicated that DAPA improved renal function, reduced fibrosis, and suppressed ferroptosis markers in diabetic mice. In vitro, DAPA inhibited ferroptosis and fibrosis in HK-2 cells under high glucose conditions. Molecular docking and network pharmacology suggested DAPA's anti-fibrotic and anti-ferroptotic effects may involve the Nrf2 and TGF-β signaling pathways. DAPA also reduced serum creatinine and blood urea nitrogen in diabetic mice, improved glomerulosclerosis and interstitial fibrosis, decreased iron deposition, and enhanced antioxidant activity. Overall, DAPA's multi-target mechanisms significantly improve DN progression, suggesting its potential as a targeted therapy against ferroptosis. Future studies should further explore DAPA's applications., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Diabetic panvascular disease (DPD) is the leading clinical complication of diabetes mellitus (DM), characterized by atherosclerosis across multiple organ vessels. It is a major cause of high disability and mortality rates in DM. However, the pathological mechanisms and key mediators of DPD remain unclear., Methods: This study constructed a single-cell organotypic atlas of the vasculature containing 321,358 cells by integrating 14 single-cell datasets from 8 major mouse organs and tissues. A total of 63 cell types were identified, including 9 vascular cell subtypes, whereas the cell-to-cell interaction (CCI) patterns of the organotypic vasculature were systematically analyzed., Results: Endothelial cells (ECs) were identified as the major cell type involved in CCI within the vasculature, with their ligands interacting with receptors of various cell types, which contribute to multiple biological processes such as stem cell differentiation and immune regulation. Notably, the study examined the cellular communication characteristics of different EC subtypes. Additionally, the inter-organ communication between the heart and kidney-key tissues in DPD-was analyzed. The BMP signaling pathway emerged as a critical communication pathway leading to cardiorenal complications in DM, with SGLT2i having a regulatory role in BMP6 modulation., Conclusions: The study provides, for the first time, a single-cell analysis of the CCI patterns of the organotypic vasculature and highlights the central role of ECs. Moreover, the key role of BMP6 in diabetic cardiorenal complications is elucidated. These findings offer new insights into the mechanisms underlying DPD co-morbidities and provide a novel scientific basis for clinical prevention, treatment strategies for DPD, and the understanding of the action mechanism of SGLT2i., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Diabetic nephropathy (DN) closely relates to morphological and functional changes of podocytes, and anaerobic glycolysis represents the predominant energy source of podocytes. However, it is unknown whether lactate accumulation in chronic high glucose causes epithelial-mesenchymal transition (EMT) of podocytes through lactate-derived histone lysine lactylation (HKla). Lactate levels increased in high glucose-stimulated mouse podocyte cell line MPC and blood and the kidney of diabetic mice. High glucose or exogenous lactate decreased nephrin levels while increased collagen IV and HKla levels in MPC, but co-treatment with oxamate or dichloroacetate reduced lactate levels and alleviated the decreases in nephrin and zonula occludens- 1 levels and the increases in collagen IV and α-smooth muscle actin as well as HKla levels in high glucose-cultured MPC. However, co-treatment with rotenone diversely affected these indices. Eleven intersection genes were screened in lactate raising and lowering interventions in podocytes using RNA sequencing and four genes were validated by qPCR. Furthermore, lactate-lowering treatments attenuated renal functions, EMT, and histone lactylation in the kidney of diabetic mice. Additionally, the increased lactate might result from the upregulated monocarboxylate transporter 2 in the mitochondria and the decreased pyruvate dehydrogenase activity. Together, we reveal the role of histone lactylation in driving the EMT phenotype of podocytes in chronic high glucose state, subsequently promoting the pathological process of DN. Our study provides a reference for the study of the relationship between lactate-induced histone lactylation modification and diabetic complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Diabetic kidney disease (DKD) is a main complication of diabetes mellitus. experimental in vitro validation and Network pharmacology were used in this study to explore the potential mechanism of Huangkui capsules (HKC) in treating DKD. First, we used CCK8 to analyze the optimal drug concentration of HKC. Next, we used flow cytometry, ELISA, Scratch test, and immunofluorescence to examine the apoptosis, oxidative stress, inflammatory factors, and fibrotic factors (FN and α-SMA) expression in HK-2 cells. Thereafter, in order to determine the potential molecular mechanisms underlying the therapeutic effect of HKC in DKD. Compounds contained in HKC were explored by UPLC-Q-TOF-MS/MS. SwissTargetPrediction was utilized for predicting potential gene targets of these compounds. OMIM, DisGeNet and GeneCards databases were employed to identify DKD-related genes. Meanwhile, the association of compounds with DKD genes was examined by protein-protein interaction, GO and KEGG analysis. Finally, molecular docking and molecular dynamics simulation were adopted for further validation. The results showed that HKC had 40 active ingredients, 1051 possible gene targets, and 133 DKD-HKC intersection genes. IL6, TNF, GAPDH, AKT1, PPARG, and TP53 were candidate hub genes by which HKC exerted its anti-DKD function based on molecular docking, molecular dynamics simulation and experimental results. To conclude, this study sheds more lights on the possible pharmacological activities of HKC in DKD and a foundation for further clinical application., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Diabetic nephropathy (DN) is one of the most common and serious microvascular complications associated with diabetes. DN is the leading contributor to the majority of cases of end-stage renal disease (ESRD). Small extracellular vesicles (sEVs) can transport various genetic materials to recipient cells. The objective of this study was to explore how sEVs released from HK-2 cells when stimulated by high glucose levels influence renal tubular phenotypic transformation through miR-21-5p., Methods: Both human and cell studies were utilized to explore the crosstalk between proximal renal tubules in DN. sEVs from plasma and cells were isolated using ultracentrifugation, and the differential expression of miR-21-5p in plasma sEVs from DN patients versus healthy controls was quantified using Quantitative Real-time PCR (RT-qPCR). A DN model was constructed by stimulating HK-2 cells with glucose. The expression of epithelial-mesenchymal transition (EMT) proteins in each cell group was analyzed by Western Blot (WB), while miR-21-5p levels in both cells and their sEVs were quantified using RT-qPCR. A stable transfected HK-2 cell line was constructed. The CCK8 assay, scratch assay, and WB were employed to detect EMT proteins, aiming to explore how autocrine sEVs affect tubular phenotypic transformation in diabetic nephropathy (DN)., Results: The expression of miR-21-5p in plasma sEVs was significantly elevated in the DN group compared to the healthy control group. High glucose (HG) stimulation of HK-2 cells resulted in higher miR-21-5p expression in both cells and their sEVs, leading to enhanced proliferation, migration, and EMT capacities in these cells. Co-incubation of HK-2 cells with HG-sEVs significantly enhanced the proliferation, migration, and EMT capabilities of the recipient cells, but miR-21-5p knockdown reversed these effects., Conclusion: These results indicate that high glucose stimulates HK-2 cells to secrete sEVs, which promote DN proliferation, migration, and EMT through miR-21-5p, thereby offering new insights into the treatment of DN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear., Methods: The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits., Results: Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin., Conclusion: Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Chronic inflammation and immune imbalance mediated by macrophages are considered pivotal in diabetic kidney disease (DKD). The study aims to clarify the macrophage heterogeneity and phenotype dynamics, and pinpoint critical targets within efferocytosis in DKD., Methods: Utilizing early human DKD sequencing data, we computed the potential communication between leukocytes and renal intrinsic cells. Subsequently, we scrutinized the single-cell RNA sequencing (scRNA-seq) data from CD45-enriched immune cells, concentrating on the macrophage subsets in DKD. Pseudotime trajectory analysis was conducted to explore cell development. Differential expression genes (DEGs) from macrophage subgroups and bulk RNA-sequencing were used to identify shared hub genes. The NephroseqV5 platform was employed to evaluate the clinical significance, and the expression of key molecules was validated in DKD tissues., Results: Macrophage infiltration rose in DKD, causing inflammation through the release of chemokines. As time progressed, the number of resident macrophages substantially dropped, with diminishing M1-like and increasing M2-like phenotypes relative to early stages. Further analysis pointed to the most enrichment of macrophage function is the phagosome. We overlapped the DEGs with efferocytosis-related genes and identified key genes, including CD36, ITGAM, and CX3CR1, which exhibited significant correlations with macrophages and T cells. The Nephroseq database revealed that they are associated with proteinuria and renal function. Consistent with the validation set, in vivo experiments verified elevated expression levels of key molecules., Conclusions: In essence, our research elucidated the dynamics in macrophage subtype transitions. It emphasized three pivotal genes as critical modulators of macrophage efferocytosis in DKD, indicating their potential as innovative biomarkers and therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Zhang, Wu, Wang, Gao, Liu, Lin and Yu.)

Background: Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease, and while lifestyle interventions like intermittent fasting have shown promise in treating diabetes, the impact of modified alternate-day fasting (MADF) on DKD is not well understood. This study aimed to explore MADF's effects on DKD in db/db mice, a model for the condition, and to investigate its underlying mechanisms., Methods: We implemented an MADF regimen in db/db mice on a high-fat diet, measuring blood glucose, body weight, and renal function at various times. After the intervention, we analyzed the proteome and metabolome of renal tissues., Results: MADF was found to reduce hyperglycemia and slow the pathological progression of DKD in the mice. Proteomic analysis identified 165 proteins that increased and 196 that decreased in the kidneys of db/db mice compared to controls. MADF intervention led to a decrease in 26 of the increased proteins and an increase in 18 of the decreased ones. Notably, many of these proteins, including cathepsin S (CTSS), were related to lysosomes, suggesting a role in renal protection. Metabolomic profiling revealed changes in metabolites associated with inflammation, such as prostaglandin A1, which was downregulated in db/db mice and upregulated with MADF. Western blotting, immunohistochemistry, and immunofluorescence staining confirmed the expression changes of CTSS observed in the proteomic data. Additionally, CTSS expression was found to increase in renal cells exposed to high glucose and palmitic acid., Conclusion: MADF appears to mitigate the progression of DKD, with proteomic evidence pointing to lysosome-related proteins like CTSS as potential mediators of its renal protective effects. These findings indicate that MADF and the inhibition of CTSS could be considered as novel therapeutic strategies for DKD treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Zeng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recently, microRNAs (miRNAs) have been found to mediate the development of diabetic kidney disease (DKD) by regulating podocyte injury. The aim of this study was to investigate the influence of miR-504-3p on high glucose (HG)-treated mouse renal podocytes (MPC5) and its potential regulatory mechanisms. First, a DKD cell model was established. Next, RT-qPCR was performed to measure miR-504-3p and HNF1 Homeobox B (HNF1B) expression levels. Additionally, the proliferation and apoptosis of MPC5 cells were assessed using CCK-8 assay and Flow cytometry, respectively. The protein expression levels of cell fibrotic markers, podocyte injury marker, epithelial-mesenchymal transition (EMT) markers and HNF1B were measured by Western Blotting. ROS, MDA, SOD and GSH kits were used to assess oxidative stress levels. Furthermore, the interplay between miR-504-3p and HNF1B was confirmed by luciferase reporter experiments. The miR-504-3p expression was significantly upregulated in GEO database (GSE161884) and in HG-induced MPC5 cells. The results revealed that HG treatment decreased MPC5 cell proliferation, promoted cell apoptosis and fibrosis, and ultimately led to podocyte injury. However, miR-504-3p knockdown could reverse these phenotypes and reduce podocyte injury. Moreover, online database screening combined with dual luciferase reporter assay confirmed HNF1B as a specific target of miR-504-3p. Finally, overexpression of HNF1B mitigated the proliferation inhibition and apoptosis promotion induced by oxidative stress and inhibited EMT-mediated cell fibrosis, thereby counteracting the effects of miR-504-3p on podocyte injury under HG treatment. In summary, our data indicate that miR-504-3p regulates HG-induced podocyte injury by sponging HNF1B, providing a new direction for the treatment of DKD., Competing Interests: Declarations. Ethical approval: Not applicable. Informed consent: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Aims: Sigma-1 receptor (S1R) activation was recently identified as a promising target for preventing diabetic nephropathy (DN) by mitigating hypoxia, oxidative stress, and inflammation. This study aimed to investigate the potential reno-protective effect of the S1R agonist afobazole against streptozotocin (STZ)-induced DN in rats compared to metformin., Materials and Methods: Rats were split into six groups: the normal control group; the diabetic control group received STZ (55 mg/kg i.p.); the other four groups received STZ and were treated with different doses of either afobazole (10, 15, and 20 mg/kg) or metformin (200 mg/kg). Metabolic parameters and renal function were assessed. Expression levels of oxidative stress markers and inflammatory cytokines were measured using ELISA, apoptosis-related proteins were evaluated using immunohistochemistry, and gene expression of S1R, Nrf2, NF-κB, and TLR-4 was determined. Histopathological analysis was performed on kidney tissues., Key Findings: Both afobazole and metformin exerted hypoglycemic effects, alleviating renal injury, reducing blood urea nitrogen (BUN) and serum creatinine, and restoring oxidant/antioxidant balance in diabetic rats. Both treatments boosted renal S1R and Nrf2 levels, suppressed inflammatory proteins and cytokines, and reduced apoptotic features., Significance: The study revealed that afobazole provided nephroprotection in STZ-induced DN through a hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic potential mediated by activating the S1R/Nrf2 antioxidant axis. The 15 mg/kg dose elicited the most pronounced nephroprotective effects, outperforming other treatment groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus. Pyroptosis is a type of programmed cell death that is closely related to the development of DN, however the molecular mechanism of pyroptosis in the development of DN is still unclear. The aim of this study is to identify pyroptosis-related potential biomarkers and competing endogenous RNA (ceRNA) networks in DN. The differentially expressed pyroptosis-related genes (DEPRGs) were identified using R software from Gene Expression Omnibus (GEO) database. In total, 4 significantly upregulated hub DEPRGs (CASP1, TXNIP, IRF9, and TRAF3) were selected and verified by machine learning techniques. Receiver Operating Curve (ROC) to assess the diagnostic value of pivotal DEPRGs. Immune infiltration was analysed using the CIBERSORT algorithm in R software. Then, differentially expressed miRNAs (DEmiRNAs) and lncRNAs (DElncRNAs) were obtained from the GEO database, respectively. The hub DEPRGs-associated ceRNA network was constructed. Finally, DN rats were induced by high-sugar and high-fat diet combined with an intraperitoneal injection of STZ. The expression of pyroptosis-related proteins and 4 hub DEPRGs were detected in rats' kidney tissues using Western blotting. The DN pyroptosis-related ceRNA networks constructed by hub genes were validated both in clinical samples and DN rat model using real-time PCR (qRT-PCR). Our results indicated that the ceRNA network consisting of key genes might be a potential regulatory axis for pyroptosis in DN., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus; oxidative stress plays a key role in the pathogenesis of DN. The objective of this study was to evaluate the antioxidant effect of vitamin E on diabetic nephropathy. A control group and three groups of rats with streptozotocin-induced diabetes mellitus (untreated diabetic rats and diabetic rats treated with vitamin E 250 and 500 mg/kg) were studied. After 4 weeks of treatment, the kidneys were removed under anesthesia with sodium pentobarbital. The kidneys were weighed, the AT 1 and AT 2 receptor expression was measured by Western blot, and the activities of glutathione peroxidase, catalase, and superoxide dismutase were determined in the renal cortex. Rats with diabetes mellitus had hyperglycemia, increased food and water consumption, and higher urinary volume than control rats. In diabetic rats (DM), kidney hypertrophy was observed and measured by kidney weight, protein/DNA ratio in the renal cortex, and proximal tubular cell area; proteinuria and reduced creatinine clearance were observed. AT 1 and AT 2 receptor expression in the kidney cortex of DM rats increased significantly compared to normoglycemic rats; antioxidant enzyme activities were decreased; treatment with vitamin E reversed kidney hypertrophy and reduced proteinuria; reduction in expression of AT 1 and AT 2 receptors was associated with increased antioxidant activity. Thus, treatment with vitamin E slows the progress of DN.

Ectopic lipid deposition, mitochondrial injury, and inflammatory responses contribute to the development of diabetic kidney disease (DKD); however, the mechanistic link between these processes remains unclear. In this study, we demonstrate that the ceramide synthase 6 (CerS6) is primarily localized in podocytes of the glomeruli and is upregulated in two different models of diabetic mice. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses in male diabetic mice and in male mice with adriamycin-induced nephropathy. In contrast, podocyte-specific overexpression of CerS6 sufficiently induces proteinuria. Mechanistically, CerS6-derived ceramide (d18:1/16:0) can bind to the mitochondrial channel protein VDAC1 at Glu59 residue, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and ultimately promoting an immune-inflammatory response in the kidney. Importantly, CERS6 expression is increased in podocytes from kidney biopsies of patients with DKD and focal segmental glomerulosclerosis (FSGS), and the expression level of CERS6 is correlated negatively with glomerular filtration rate and positively with proteinuria. Thus, our findings suggest that targeting CerS6 may be a potential therapeutic strategy for proteinuric kidney diseases., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Diabetic nephropathy (DN) is characterized by glomerular basement membrane (GBM) thickening, primarily due to the abnormal accumulation of collagen type IV (COL4) in the extracellular matrix (ECM) of podocytes. Podocytes endocytosis is crucial for maintaining COL4 balance and GBM integrity. Previous studies have shown that G protein-coupled receptor 107 (GPR107) facilitates clathrin-dependent transferrin internalization and recycling in murine embryonic fibroblast cells. Therefore, the aim of the study is to investigate the role of GPR107 in regulating COL4 balance within the podocytes ECM and its potential as a therapeutic target for DN. Here, we found a significant decrease in GPR107 expression in renal tissues from DN patients and streptozocin (STZ)-induced DN mice. Furthermore, GPR107-deficient mice with STZ-induced DN exhibited more severe kidney damage, marked by increased GBM thickening and COL4 accumulation. In vitro, GPR107 deficiency under high-glucose conditions promoted COL4 accumulation in the ECM of podocytes due to increased COL4 production and decreased COL4 degradation. Mechanistically, we demonstrated that GPR107 contributes to angiotensin II receptor type 1 (AT1R) internalization through clathrin-mediated endocytosis (CME) in podocytes. Therefore, GPR107 deficiency impairs AT1R internalization, leading to increased membrane-bound AT1R. This, in turn, activates the AT1R/Ca 2+ signaling pathway to promote phosphorylation of cAMP-response element-binding protein (CREB), ultimately enhancing COL4 synthesis and inhibiting the expression of matrix metalloproteinase 2 (MMP-2). These findings shed light on new functions of GPR107 in DN and offer new insights into a therapeutic target for DN., Competing Interests: Declarations. Ethics approval and consent to participate: Human biopsy collection was approved by the Biomedical Ethics Committee of Anhui Medical University (approval no. 83230321) and conformed to the ethical standards for medical research involving human subjects, as laid out in the 1964 Declaration of Helsinki and its later amendments. All animal experiments followed the WMA Statement on animal use in biomedical research and approved by the Experimental Animal Ethics Committee of Anhui Medical University (approval no. LLSC20230628). Written informed consent was obtained from all participants. Consent for publication: Informed consent was obtained from all the subjects involved in the study. Competing interests: All authors declare no competing interests., (© 2025. The Author(s).)

Sterile inflammation resulting in an altered immune response is a key determinant of renal injury in diabetic nephropathy (DN). In this investigation, we evaluated the hypothesis that hyperglycemic conditions augment the pro-inflammatory immune response in the kidney by promoting podocyte-specific expression of the stress response protein regulated in development and DNA damage response 1 (REDD1). In support of the hypothesis, streptozotocin (STZ)-induced diabetes increased REDD1 protein abundance in the kidney concomitant with renal immune cell infiltration. In diabetic mice, administration of the SGLT2 inhibitor dapagliflozin was followed by reductions in blood glucose concentration, renal REDD1 protein abundance, and immune cell infiltration. In contrast with diabetic REDD1 +/+ mice, diabetic REDD1 -/- mice did not exhibit albuminuria, increased pro-inflammatory factors, or renal macrophage infiltration. In cultured human podocytes, exposure to hyperglycemic conditions promoted REDD1-dependent activation of NF-κB signaling. REDD1 deletion in podocytes attenuated both the increase in chemokine expression and macrophage chemotaxis under hyperglycemic conditions. Notably, podocyte-specific REDD1 deletion prevented the pro-inflammatory immune cell infiltration in the kidneys of diabetic mice. Furthermore, exposure of podocytes to hyperglycemic conditions promoted REDD1-dependent pyroptotic cell death, evidenced by an NLRP3-mediated increase in caspase-1 activity and LDH release. REDD1 expression in podocytes was also required for an increase in pyroptosis markers in the glomeruli of diabetic mice. The data support that podocyte-specific REDD1 is necessary for chronic NF-κB activation in the context of diabetes and raises the prospect that therapies targeting podocyte-specific REDD1 may be helpful in DN., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: All procedures adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Penn State College of Medicine Institutional Animal Care and Use Committee (PROTO202302452)., (© 2025. The Author(s).)

Cubebin, a dibenzyl butyrolactone lignan belonging to several distinct families, including Aristolochiaceae, Myristicaceae, Piperaceae, and Rutaceae, and possesses several pharmacological activities, including analgesic, anti-inflammatory, antioxidant, and vasodilatory. The current study aimed to evaluate the effect of cubebin on streptozotocin (STZ)-evoked diabetic nephropathy (DN). DN is a well-identified complication of diabetes mellitus (DM) characterized by renal hypertrophy that progressively declines kidney function. Wistar rats were randomly divided into groups- normal, STZ control (65 mg/kg/body weight), and STZ + cubebin (10 and 20 mg/kg). Biochemical parameters such as glucose levels, kidney parameters, lipid profile, oxidative stress, endogenous antioxidant markers, inflammatory cytokines and histopathology were performed. Molecular docking [(PDB ID: TNF-α (7JRA), NF-κB (1SVC), TGF-β1 (3TZM)] and dynamic simulation (MDS) were also performed with the selected target. STZ-induced DN was changes in these parameters. In contrast, DN + cubebin at 10 and 20 mg/kg doses improved the biochemical parameters and histological changes. Furthermore, molecular docking and simulation studies showed a binding affinity with negative binding energy with TNF-α (7jra, - 11.342 kcal/mol), TGF-β1 (3tzm, - 9.162 kcal/mol) and NF-κB (1svc, - 6.665 kcal/mol). The results of MDS provided insight into the mechanisms that associate proteins TNF-α, NF-κB, and TGF-β1 in conformational dynamics upon binding to cubebin. In conclusion, these findings exhibit a potential effect of cubebin in STZ-evoked DN rats., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Abnormal Wnt5a expression, mitochondrial abnormalities and calcium overload have been detected in many metabolic diseases. However, the association of Wnt5a-Ca 2+ and mitochondrial dysfunction in diabetic nephropathy (DN) progression remains unknown. We used streptozotocin-induced DBA2/J male mice as a DN model. The mice were treated with losartan (10 mg/kg/d*12 w) or losartan (10 mg/kg/d*12 w) + levamlodipine (5 mg/kg/d*12 w). High glucose (HG) (40 mmol/L)-induced HK-2 cells were used for in vitro experiments. Wnt5a and mitochondrial calcium uniporter (MCU) expression, mitochondrial dynamics, morphological changes and Ca 2+ concentration were detected in different groups. Levamlodipine, a kind of calcium channel blocker, in combination with losartan ameliorated tubular injury and reversed mitochondrial fragmentation and dynamic dysfunction more efficiently than losartan alone in diabetic mice. Wnt5a induced Ca 2+ uptake and aggravated mitochondrial fusion-fission disorder in HG-stimulated HK-2 cells. In addition, increased MCU formation was found in the mitochondria of tubular cells under HG stimulation and was upregulated by the activation of the Wnt5a-Ca 2+ pathway. Our study showed that the Wnt5a-Ca 2+ signalling pathway was involved in Ca 2+ overload-induced mitochondrial dysfunction possibly through MCU in tubular injury and DN progression. A calcium channel blocker in combination with a renin-angiotensin system inhibitor (RASi) could be a promising therapeutic strategy in DN patients., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

APOL1 Renal Risk Variants (APOL1RRVs, G1, and G2) are known to be toxic to glomerular podocytes and causally associated with an enhanced prevalence and progression of many different etiologies of chronic kidney disease (CKD), leading to the delineation of a new disease designation of APOL1-Mediated Kidney Disease (AMKD). Notably, APOL1RRVs have not consistently been shown to increase the prevalence or severity of diabetic kidney disease (DKD) progression, which is the most common cause of End-Stage Kidney Disease (ESKD). While this apparent discrepancy seems perplexing, its clarification should provide important mechanistic and therapeutic insights. Activation of the Renin-Angiotensin System (RAS) plays a critical role in the development and progression of DKD. Recent in vitro and in vivo studies also demonstrated that RAS activation contributes to kidney cell injury in AMKD experimental models. Both high glucose, as well as APOL1RRVs escalate the podocyte expression of miR193a, a known mediator of glomerulosclerosis, including idiopathic Focal Segmental Glomerular Sclerosis (FSGS) and DKD. We propose that either the RAS and/or miR193a levels in the diabetic milieu are already maximally conducive to kidney target cell injury and, therefore, are agnostic to further injury in response to APOL1RRVs. Similarly, the contributory role of hypertension (which is frequently reported as the second most common cause of ESKD) in the progression of AMKD remains a controversial issue. Since several clinical reports have shown that controlling hypertension does not consistently slow the progression of AMKD, this has led to a formulation wherein APOL1-RRVs primarily lead to kidney injury with accompanying hypertension. Notably, half a decade later, the notion that hypertension is not a cause but rather a consequence of kidney injury was contested by investigators analyzing the Mount Sinai BioMe repository, a comprehensive clinical and genetic database including participants with APOL1RRVs. These investigators observed that hypertension predated the observed decline in GFR in individuals with APOL1RRVs by ten years. In the present study, we discuss the mechanistic forces that may underpin the gaps in these clinical manifestations, which did not allow the temporal association of hypertension with AMKD to be translated into causation and may also dissociate DKD and AMKD. We have hypothesized models that need to be validated in future experimental studies.

The effacement of podocyte foot processes, which form slit diaphragms, are common features of proteinuria. Exploring podocyte energy metabolism, especially under diabetic conditions, may offer insights into the pathogenesis of diabetic kidney disease. Lipid accumulation is recognized as a cause of podocyte cytoskeleton remodeling and insulin resistance. Thus, the role of the metabolic sensor G-protein-coupled receptor 81 (GPR81) was examined in the molecular pathway of lipid accumulation in podocytes under hyperglycemic conditions. It was discovered that hyperglycemia downregulated the cyclic adenosine monophosphate/protein kinase A signaling pathway, which downregulated the expression of adipose triglyceride lipase (ATGL). Perilipin 1 was also downregulated; simultaneously, lipid droplet accumulation was enhanced. Glycerol and free fatty acid concentrations were also reduced, providing evidence of lipolysis inhibition. Interestingly, the expression of GPR81 decreased under hyperglycemia conditions despite the evidence of its activation, indicating strict lipolysis regulation. More importantly, cell functions were altered, reflected by an increase in albumin permeability and rearrangement of the actin cytoskeleton. The effect of ATGL activity inhibition on lipolysis, actin cytoskeleton arrangement, and permeability of the podocyte monolayer was investigated. The results were similar to GPR81 downregulation. Altogether, the present data indicate that GPR81 is likely a crucial part of the lipid sensing system, and its alterations during hyperglycemia might contribute to glomerular filtration barrier deterioration in diabetic kidney disease., (© 2025 Wiley Periodicals LLC.)

Lipotoxicity plays a crucial role in the progression of diabetic kidney disease (DKD), yet the dynamic changes in renal lipid composition from diabetes to early-stage DKD remain unclear. Free fatty acids, lactosylceramides and cardiolipin (CL) were identified as the most significantly altered lipids by quantitatively comparing targeted lipids in the renal cortex of the classic spontaneous diabetic db/db mice using high-coverage targeted lipidomics. Further investigation into the causes and effects of decreased CL, which is a unique mitochondrial phospholipid, was conducted in mitochondria-rich renal proximal tubular cells by using western blotting, real-time PCR, immunohistochemistry and transmission electron microscopy. Reduced expression of cardiolipin synthase, a key enzyme in the CL synthesis pathway, and inhibition of CL-related mitophagy were confirmed under high glucose conditions. In addition, the protective effect of CL-targeted Szeto-Schiller 31 in preserving mitophagy was demonstrated in both in vivo and in vitro studies. These findings provide new insights into the pathogenesis of early-stage DKD from a lipid perspective and offer a theoretical basis for discovering new treatments., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Aims: We aim to explore the potential of nicotinamide n-methyltransferase (NNMT) as a sensitive marker of renal tubular injury and the possibility of an NNMT inhibitor to combine with sodium-glucose cotransporter 2 (SGLT2) inhibitor to protect proximal tubular epithelium in vivo and in vitro model of Type 2 diabetes mellitus (T2DM), respectively., Methods: In vivo, immunohistochemical staining, Masson's trichrome staining and Sirius red staining were used to observe the changes of NNMT expression, renal tubular injury and interstitial fibrosis in renal tissue from the db/db mice. Bioinformatic analysis was also conducted to broaden the range of data validation. In vitro, Western Blot and quantitative RT-PCR were used to measure the degree of damage of HK-2 cells., Results: Our in vivo data showed upregulation of NNMT expression paralleled renal tubular damage and interstitial fibrosis. Our in vitro data revealed both NNMT inhibitors and SGLT2 inhibitors can protect against the injury as assessed by extracellular matrix (ECM) synthesis and profibrotic phenotype transition of HK-2 cells, and the combination of these two agents can further reduce these injuries., Conclusions: The present study is the first to show that NNMT is a promising marker of renal tubular injury in diabetic nephropathy (DN) and NNMT inhibitors can synergize with SGLT2 inhibitors to protect HK-2 better. Our findings will provide the insight and pave the way of developing novel therapeutic strategies for chronic renal tubular injury associated with T2DM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Oxidative stress (OS) and inflammation play essential roles in the development of diabetic nephropathy (DN). Tirzepatide (TZP) has a protective effect in diabetes. However, its underlying mechanism in DN remains unclear. DN model mice were induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg), followed by administration of different doses of TZP (3 and 10 nmol/kg) via intraperitoneal injection for 8 weeks. The effects of TZP on DN were evaluated by detecting DN-related biochemical indicators, kidney histopathology, apoptosis, OS, and inflammation levels. Additionally, to further reveal the potential mechanism, we investigated the role of TZP in modulating the IL-17 pathway. TZP reduced serum creatinine (sCR), blood urea nitrogen (BUN), and advanced glycosylation end products (AGEs) levels, while simultaneously promoting insulin secretion in diabetic mice. Additionally, TZP attenuated tubular and glomerular injury and reduced renal apoptosis levels. Further studies found that TZP increased the levels of SOD and CAT, and decreased MDA. Meanwhile, TZP also reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both mouse serum and kidney homogenates. TZP effectively inhibited the IL-17 pathway, and subsequent intervention with an IL-17 pathway agonist (IL-17A) reversed the suppressive effects of TZP on OS and inflammation. TZP can improve DN by inhibiting OS and inflammation through the suppression of the IL-17 pathway., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethics approval and consent to participate: The animal experiments were approved by the local ethical committee in accordance with the ARRIVE guidelines. Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, commonly utilized for diabetic nephropathy, have demonstrated benefits beyond glucose control, including organ protection. This study investigated the protective effects of the SGLT2 inhibitor, dapagliflozin (DAPA), on palmitate-induced renal tubular epithelial cell (HK-2) injury, particularly concentrating on mitochondrial function and oxidative stress. HK-2 cells were treated with 150 μmol/L palmitate to induce mitochondrial dysfunction and oxidative stress, and they were co-treated with 2 μmol/L DAPA for 24 h. DAPA significantly increased cell viability (P < 0.05), reduced reactive oxygen species (ROS) levels (P < 0.001), and restored mitochondrial membrane potential (P < 0.05). It also lowered malondialdehyde (MDA) level (P < 0.001) and increased superoxide dismutase (SOD) expression level (P < 0.001). Western blot analysis revealed that DAPA reversed palmitate-induced upregulation of apoptosis-related proteins, including Bax and Cytochrome C. DAPA also mitigated the overactivation of autophagy-related proteins, such as LC3 and Beclin-1, indicating its role in modulating autophagy under diabetic nephropathy. Electron microscopy confirmed improvements in mitochondrial morphology, accompanying by reduced swelling and restored cristae structure. These findings highlight the potential of DAPA, as an SGLT2 inhibitor, to mitigate renal injury by enhancing mitochondrial function and reducing oxidative stress, providing novel insights into its therapeutic value for diabetic nephropathy management., Competing Interests: Declaration of competing interest Each named author has substantially contributed to conducting the underlying research and drafting this manuscript. Additionally, to the best of our knowledge, the named authors have no conflict of interest, financial or otherwise., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To investigate the role of silent information regulator 6 (SIRT6) in regulating podocyte injury in diabetic nephropathy (DN) through autophagy mediated by Notch signaling pathway. A blank control group (group A), a diabetic nephropathy group (group B), and a Sirt6 intervention group (group C) were established. The group A cells were human normal glomerular podocyte cell lines (HGPCs) without any treatment. In group B, the cells were cultivated in glucose medium containing 30 mmol/L and a 10 µmol/L anti-LSirt6 antibody solution. Three sets of cells were tested for their capacity to proliferate via CCK8, for protein expression via Western blot, for associated mRNA expression levels via qPCR, and for cell migration and invasion ability via Transwell. The podocyte proliferation and migration activity in group B were reduced compared to group A, while these properties in group C were elevated compared to group B (DN). B Group is diabetes nephropathy. Compared with those in group B, the number of invading podocytes in group C were greater than those in group A, and the overall apoptosis rate in group C was lower than that in group B. The expression levels of apoptotic proteins in the podocytes in group C were greater than those in group B, and the bcl-2 level was lower than those in group B. The Notch1 and Jagged1 mRNA and protein levels in the podocytes in group B were greater than those in group A, whereas those in the podocytes in group C were lower than those in group B. Sirt6 can protect against podocyte autophagy injury in DN by regulating the Notch1 signaling pathway., Competing Interests: Declarations. Ethics approval and consent to participate: All experimental protocols were approved by the Tianjin 4th Center Hospital. All methods were carried out in accordance with relevant guidelines and regulations. All methods are reported in accordance with ARRIVE guidelines. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Traditional Chinese Medicine (TCM) has demonstrated promising efficacy in managing and preventing the early‑stage diabetic nephropathy (DN). Although the exact mechanisms remain elusive, clinical evidence has suggested that Jinlida granules (JLD) are beneficial in improving renal function among patients with DN. The present study aimed to elucidate the effect of JLD on DN and the underlying molecular mechanism. Therefore, podocyte apoptosis was evaluated using flow cytometry and TUNEL staining, while mitochondrial morphology and function were assessed using transmission electron microscopy, MitoTracker, JC‑1 and reactive oxygen species staining. RNA sequencing analysis was performed to elucidate the mechanism underlying the effect of JLD on DN. Additionally, to investigate the role of peroxisome proliferator‑activated receptor‑γ co‑activator‑1α (PGC‑1α) in mitigating JLD‑induced mitochondrial dysfunction and podocyte apoptosis, MPC5 cells were transfected with the corresponding small interfering RNA constructs. The results showed that JLD effectively improved renal function and mitigated podocyte injury, as well as ameliorated mitochondrial dysfunction and inhibited apoptosis in db/db mice. In vitro experiments further revealed that JLD exerted a protective effect via inhibiting mitochondrial fission and apoptosis in high glucose‑treated podocytes. Furthermore, JLD enhanced the phosphorylation of adenosine monophosphate‑activated protein kinase (AMPK), thus promoting the expression of PGC‑1α, eventually improving apoptosis and mitochondrial homeostasis. Overall, the current study revealed that JLD could improve mitochondrial homeostasis and reduce cell apoptosis in podocytes via activating the AMPK/PGC‑1α pathway, thus providing a theoretical foundation for the clinical management of DN.

Intestinal microbiota are pathophysiologically involved in diabetic nephropathy (DN). Dapagliflozin, recognized for its blood glucose-lowering effect, has demonstrated efficacy in improving DN. However, the mechanisms beyond glycemic control that mediate the impact of dapagliflozin on DN remain unclear. Here, we investigated the effects of dapagliflozin on DN and gut microbiota, elucidating how it mitigates DN via the gut-kidney axis. Low-dose dapagliflozin markedly ameliorated renal inflammation and fibrosis and improved gut barrier function in high-fat diet (HFD)/streptozotocin (STZ)-induced DN mice and db / db mice without affecting blood glucose levels. These effects were associated with altered gut microbial composition and function. Eradication of the resident microbiota abolished the protective effects of dapagliflozin against kidney injury in DN mice. Moreover, dapagliflozin significantly altered microbial metabolites in DN mice, decreasing argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S -allylcysteine (SAC) levels. ASA and PA increased the expression of renal inflammation- and fibrosis-related markers in HK-2 cells, whereas SAC ameliorated renal damage and altered the microbial composition in a manner similar to dapagliflozin in DN mice. Notably, Muribaculaceae and Desulfovibrionaceae were correlated with the alleviation of DN-associated renal dysfunction by low- and high-dose dapagliflozin treatments in DN mice. These findings demonstrate a potential application of dapagliflozin in managing DN by targeting the gut microbiota. NEW & NOTEWORTHY We demonstrated that dapagliflozin administration alleviated renal inflammation and fibrosis in vivo and in vitro, along with reshaping the gut microbiota composition and altering levels of key microbial metabolites, including argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S -allylcysteine (SAC). Importantly, the genera Muribaculaceae and Desulfovibrionaceae emerged as pivotal microbial genera mediating the protective effects of dapagliflozin against diabetic nephropathy.

Podocytes can undergo PANoptosis (apoptosis, pyroptosis, and necroptosis). Diabetic kidney disease (DKD) is the leading cause of kidney failure, and podocyte loss is a major event leading to the progression of DKD. Here, we compared single cell RNA sequencing (scRNA-seq) data between three normal and three DKD human kidney samples and found a significant increase of TNFSF10 and TNFRSF10B expression in podocytes of patients with DKD. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), coded by TNFSF10, belongs to the TNF superfamily members and TNFRSF10B codes for death receptor 5 (DR5). We confirmed that expression of TRAIL and DR5 increased in podocytes of patients with DKD and correlated with the severity of DKD. In vitro, TNF-α stimulated TRAIL and DR5 expression in cultured human podocytes. Silence of TRAIL or DR5 by small interfering RNA alleviated TNF-α-stimulated podocytes PANoptosis, while overexpression of TRAIL, treatment with recombinant human TRAIL (rh-TRAIL) or the DR5 activator (Bioymifi) enhanced podocytes PANoptosis. In vivo, podocyte-specific deletion of TNFSF10 or TNFRSF10B alleviated podocyte and glomerular injury in high fat diet and streptozotocin-induced obese diabetic mice and was associated with decreased podocyte PANoptosis. Conversely, the induction of TNFSF10 overexpression specifically in podocytes exacerbated albuminuria and kidney injury in diabetic mice with increased podocyte PANoptosis. Additionally, administration of soluble DR5-Fc, an inhibitor of DR5, resulted in a marked reduction in albuminuria and glomerular injury in BTBR ob/ob mice. Our findings suggest a critical autocrine role of TRAIL/DR5 in inducing podocyte injury in DKD via activation of PANoptosis., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Diabetic nephropathy (DN) is a common complication of diabetes and a leading cause of end-stage renal disease, characterized by progressive kidney fibrosis and inflammation. The transforming growth factor-beta (TGF-β) signaling pathway plays a crucial role in the pathogenesis of diabetes nephropathy, and SMAD7 is a key negative regulator of this pathway. Recent studies have highlighted the involvement of miRNA in the progression of DN. Computational analysis identified 11 potential miRNAs such as miR-424, miR-195, miR-216a, miR-503, miR-15a-5p, miR-15b-5p, miR-665, miR-520h, miR16-5p, miR-21 and miR-32-5p which are predicted to target 3'UTR of SMAD7 mRNA. This review aims to explore the role of these miRNAs in the progression of DN. Notably, these miRNAs have shown therapeutic potential in mitigating fibrosis and inflammation by modulating SMAD7 expression in DN. Future directions can be to investigate the mechanistic pathways through which these miRNAs exert their effects, as well as optimizing delivery systems for effective clinical application. Targeting miRNAs that modulate SMAD7 expression represents a promising strategy for developing specific and effective therapies for diabetic nephropathy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, inflammation and fibrosis play an important role in its progression. Histone lysine crotonylation (Kcr) was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of sodium crotonate (NaCr) and histone Kcr in kidney diseases. However, the effects of NaCr and NaCr-induced Kcr on DKD remain unclear. In this study, db/db mice and high glucose-induced human tubular epithelial cells (HK-2) were used respectively, and exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention reagents, histone Kcr and DKD-related indicators were detected. The results confirmed that NaCr had an antidiabetic effect and decreased blood glucose and serum lipid levels and alleviated renal function and DKD-related inflammatory and fibrotic damage. NaCr also induced histone Kcr and histone H3K18 crotonylation (H3K18cr). However, NaCr and Cr-CoA-induced histone Kcr and protective effects were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300 in vitro. In summary, our data reveal that NaCr may mitigate DKD via an antidiabetic effect as well as through ACSS2 and P300-induced histone Kcr, suggesting that Kcr may be the potential molecular mechanism and prevention target of DKD., Competing Interests: Declarations. Ethics Approval and Consent to Participate: Animal experiments were approved by the Institutional Animal Ethics Committee of Southwest Medical University. Conflicts of Interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease (ESRD), but its mechanism has not been clearly studied. We utilized integrative transcriptome analysis to explore the pathogenesis of DN., Methods: We conducted an analysis by combining bulk dataset and single-cell transcriptome dataset. Through this approach, we identified that Serpine2 may regulate the 'collagen-containing extracellular matrix' pathway involved in DN. Subsequently, we established DN animal and cell models using db/db mice and mesangial cells (MCs) to validate the role of Serpine2 in DN. In the animal model, we detected the expression level of Serpine2 in DN using western blotting (WB) and immunofluorescence (IF) assays. To further clarify the molecular mechanism of Serpine2 in DN, we knocked down Serpine2 and observed its effects on MCs proliferation and extracellular matrix (ECM) accumulation., Results: Our single-cell analysis of DN models highlighted a pivotal role for MCs in the disease's initiation. Next, through Cytoscape analysis of differentially expressed genes (DEGs) in MCs, we identified the following 10 hub genes: Acta2, Angpt2, Ccn1, Col4a1, Col4a2, Col8a1, Kdr, Thbs1, Tpm4 and Serpine2. Subsequently, we identified that Serpine2 and Kdr were also significantly DEGs in the bulk analysis of glomeruli. Additionally, our integrated gene set enrichment analysis of bulk dataset and single-cell RNA dataset revealed that the 'collagen-containing extracellular matrix' was a key pathway in DN progression. Serpine2 was one of the crucial genes involved in regulating this pathway. Therefore, we speculated that the regulation of the 'collagen-containing extracellular matrix' pathway by Serpine2 was an important mechanism. Importantly, WB and IF staining confirmed that Serpine2 expression was upregulated in the MCs of diabetic mice. Knockdown of Serpine2 in cultured MCs alleviated high-glucose-induced excessive MCs proliferation and ECM accumulation. Finally, we found that ERK agonist Ro 67-7476 eliminated the effect of Serpine2 siRNA., Conclusions: In summary, Serpine2 regulates MCs proliferation and ECM synthesis through activation of the ERK1/2 pathway, which is an important pathogenesis mechanism of DN. These findings offer fresh perspectives on the mechanisms of glomerulosclerosis in DN pathogenesis and may provide new targets for treating DN., (© 2024 John Wiley & Sons Ltd.)

Many genetic and environmental factors are involved in the development and progression of diabetic kidney disease (DKD), and its pathology shows various characteristics. Animal models of DKD play an important role in elucidating its pathogenesis and developing new therapies. In this study, we investigated the pathophysiological features of two DKD animal models: db/db mice (background of hyperglycemia) and KK-Ay mice (background of hyperinsulinemia). Male and female mice were fed a high-fat/high-sucrose (HFS) diet for eight weeks. Two mouse models fed the HFS diet showed increases in urinary protein, kidney weight, and glomerular size, but these changes were pronounced in KK-Ay mice. Pathological examination revealed tubulointerstitial fibrosis in KK-Ay mice fed the HFS diet, but not in db/db mice. In addition, fat accumulation was observed in the macula densa of db/db mice and in the glomeruli of KK-Ay mice fed with the HFS diet. In conclusion, an HFS diet exacerbates renal lesions with tubulointerstitial fibrosis in KK-Ay mice, and KK-Ay mice fed an HFS diet are expected to be useful as a DKD model.

Aims/introduction: Diabetic kidney disease (DKD) is a major cause of kidney failure. FOS-like antigen 2 (FOSL2) has been revealed to be increased in kidney biopsies of patients with lupus nephritis, while its association with DKD remains unsolved. This study aimed to characterize the role of FOSL2 in DKD and its mechanism., Method: The kidney tissues of DKD mice induced by STZ and a high-fat diet were subjected to PAS and Masson's staining. Glomerular mesangial cells (MCs) were treated with high glucose (HG) or normal glucose (NG). CCK-8 and EdU assays were performed to detect cell proliferation, and immunoblotting was conducted to analyze ECM deposition. ChIP-qPCR was performed on MCs to detect the binding of FOSL2 on the TGF-β1 promoter and a dual-luciferase assay to detect the impact of FOSL2 on the transcription of the TGF-β1 promoter., Results: FOSL2 was elevated in the kidney tissues of DKD mice. Knockdown of FOSL2 reduced the mRNA expression of TGF-β1 to decrease the protein expression of GLUT1 and mTOR in the kidney tissues of DKD mice, and TGF-β1 reversed the effects caused by knockdown of FOSL2. The mTOR inhibitor Rapamycin alleviated kidney injury in the presence of FOSL2. Knockdown of FOSL2 inhibited the proliferation and improved ECM deposition of MCs, which were reversed by TGF-β1. Rapamycin and GLUT1 inhibitor BAY-876 reversed the promotion effect of FOSL2 on the proliferation of NG-MCs/HG-MCs and improved ECM deposition of MCs., Conclusions: Our data demonstrated that FOSL2 accentuates DKD in mice by increasing TGF-β1-induced GLUT1/mTOR signaling., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Rationale : Tubulointerstitial fibrosis is a key pathological aspect of diabetic nephropathy (DN) linked to reduced kidney function. Recent research has identified varied functions of the sigma-1 receptor (S1R) in the pathological fibrosis processes of cardiac, pulmonary, and trabecular meshwork tissues. Nonetheless, the specific roles of S1R in renal fibrosis remain inadequately understood. Objective: This study sought to examine the roles of S1R in the pathogenesis of diabetes-induced renal fibrosis, as well as to elucidate the underlying mechanisms involved. Materials and methods: S1R expression was found in DN patients, db/db mice, and HG-treated HK-2 cells. Loss-of-function studies confirmed S1R's role in nuclear factor erythroid 2-related factor 2 (NRF2) pathway-mediated ferroptosis and renal fibrosis. Molecular docking and co-immunoprecipitation (CO-IP) analysis explored the S1R-NRF2 interaction. Results: S1R was primarily found in tubular epithelial cells and was up-regulated in DN patients, db/db mice, and HG-cultured HK-2 cells. S1R inhibition alleviated ferroptosis and fibrosis in HG stimulated HK-2 cells, while knockdown of NRF2 further abolishes these protective effects by S1R inhibition. As for the further mechanism, S1R combined with NRF2 in HK-2 cells, and knockdown of S1R could increase NRF2 nuclear translocation and up-regulate the expression of phosphorylated NRF2 (p-NRF2), and finally ameliorate ferroptosis and ferroptosis-mediated renal tubular fibrosis. Conclusions: In DN, S1R expression in the kidneys is significantly elevated. It increases p-NRF2 expression, which inhibits NRF2 nuclear translocation, promoting ferroptosis in renal tubular epithelial cells and resulting in tubular fibrosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aims: Hyperuricaemia is associated with the development of Diabetic kidney disease (DKD). However, the mechanism of hyperuricaemia causing the progression of DKD remain unclear., Methods: This is a single-centre retrospective study. 155 biopsy-proven DKD patients were grouped into hyperuricaemia and non-hyperuricaemia groups. Kaplan-Meier analysis and landmark curves were performed to explore predictors of end-stage renal disease (ESRD), Cox regression analysis was used to screen for factors, a nomogram was constructed to predict the renal prognosis of DKD., Results: Patients in hyperuricaemia group had higher serum creatinine (Scr), degree of mesangial expansion and IFTA score and lower GFR, haemoglobin. SUA level was positively correlated with IFTA scores. The Kaplan-Meier curve and landmark analysis revealed worse survival in hyperuricaemia group, especially after 12 months. 11 variables, including age, sex, haemoglobin, Scr, SUA, and pathological score were collected to make a nomogram model. In the testing and training sets, the AUCs at 1, 3, and 5 years were 0.888, 0.939, and 0.886 and 0.947, 0.867, and 0.905, respectively., Conclusion: The clinicopathologic manifestation of DKD patients with hyperuricaemia was much more severe, and hyperuricaemia predicted a worse renal prognosis. A new renal prognosis prediction model including SUA was constructed for DKD with higher accuracy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Yu, Tu, Xu, Tang, Wu and Jiang.)

Background: Diabetic nephropathy (DN) is a serious condition that can result in end-stage renal failure. Recent evidence has focused on the dietary effects of polyphenols on blood glucose levels and the complications of diabetes., Objectives: In this study, we investigated the protective effect of glucosyl hesperidin (G-Hes), composed of glucose and hesperidin, against streptozotocin (STZ)-induced nephropathy in mice., Methods: We used an STZ-induced diabetic mouse model to investigate the preventive effect of G-Hes on renal pathology. After G-Hes supplementation for 4 weeks, we investigated the renal gene expression profiles using DNA microarray analysis and renal histology to examine the underlying molecular mechanism., Results: G-Hes suppressed the increase in kidney weight without any change in the blood glucose levels. This study identified 511 genes whose expression levels were substantially increased during DN development but were downregulated by G-Hes supplementation. G-Hes prevented mRNA expression associated with renal tubule injury, fibrosis, and immune responses. Notably, G-Hes supplementation considerably decreased the complement component C3 at the mRNA and protein levels in the glomeruli and ameliorated glomerular and mesangial matrix expansion in diabetic nephropathy., Conclusions: G-Hes supplementation is useful in preventing tubulointerstitial fibrosis and inflammation in a mouse model of DN, without exhibiting a hypoglycemic effect.