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Objective Design Setting Animals Methods Results Conclusions To investigate the frequency of perioperative acute kidney injury (AKI) in American Society of Anesthesiologists (SA) Grade I canine patients undergoing elective desexing using urine microscopy techniques and assess if pre‐ and intraoperative factors affect risk of developing AKI.Prospective observational clinical study conducted between September 2020 and October 2020.University teaching hospital.Thirty‐two female and four male dogs between 5 months and 5 years of age classified as ASA I undergoing elective desexing surgery.Urinalysis was performed preoperatively and 20–24 h postoperatively to identify markers of renal tubular injury (RTI), particularly the presence of granular and renal tubular epithelial cell (RTEC) casts on sediment analysis. Dogs underwent a full physical examination and a preoperative assessment including measurement of urine specific gravity (USG), packed cell volume (PCV), total plasma protein and serum creatinine (sCr) was conducted as a part of the desexing programme. Anaesthetic records were examined for any evidence of intraoperative hypotension, defined as a mean arterial pressure (MAP) of <60 mmHg for any duration of time. MAP was measured using an indirect oscillometric technique. For analysis, animals were subdivided into affected and nonaffected groups, with affected animals those that had postoperative increases in granular and RTEC casts. Categorical and comparative analyses were then performed between groups to identify associations of increased casts with pre‐, intra‐ and postoperative variables.A frequency of RTI of 5.6% was identified. This was accompanied by a significant association between increases in casts with total duration (p = 0.027) and number (p = 0.016) of hypotensive episodes.RTI is an anaesthetic consideration in ASA I veterinary patients undergoing elective desexing surgery. The identification of an association between the total duration and number of hypotensive episodes and the frequency of RTI highlights the importance of early detection of hypotension along with prompt and effective intervention in veterinary patients. [ABSTRACT FROM AUTHOR]

Background: Mutation of MMACHC gene causes cobalamin C disease (cblC), an inherited metabolic disorder, which presents as combined methylmalonic aciduria (MMA-uria) and hyperhomocysteinaemia in clinical. Renal complications may also be present in patients with this inborn deficiency. The most common histological change is thrombotic microangiopathy (TMA). However, to our acknowledge, renal tubular injury in the late-onset presentation of cblC is rarely been reported. This study provides a detailed description of the characteristics of kidney disease in cblC deficiency, aiming to improve the early recognition of this treatable disease for clinical nephrologists. Case presentation: Here we described three teenage patients who presented with hematuria, proteinuria, and hypertension in clinical presentation. They were diagnosed with renal involvement due to cblC deficiency after laboratory tests revealing elevated serum and urine homocysteine, renal biopsy showing TMA and tubular injury, along with genetic testing showing heterogeneous compound mutations in MMACHC. Hydroxocobalamin, betaine, and L-carnitine were administered to these patients. All of them got improved, with decreased homocysteine, controlled blood pressure, and kidney outcomes recovered. Conclusions: The clinical diagnosis of cblC disease associated with kidney injury should be considered in patients with unclear TMA accompanied by a high concentration of serum homocysteine, even in teenagers or adults. Early diagnosis and timely intervention are vital to improving the prognosis of cobalamin C disease. Clinical Trial Number: Not applicable. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) remains as one of the leading long-term complications of type 2 diabetic mellitus (T2DM). Studies have shown that decreased expression of glucose-6-phosphate dehydrogenase (G6PD) plays an important role in DKD. However, the upstream and downstream pathways of G6PD downregulation leading to DKD have not been elucidated. We conducted a series of studies including clinical study, animal studies, and in vitro studies to explore this. First, a total of 90 subjects were evaluated including 30 healthy subjects, 30 patients with T2DM, and 30 patients with DKD. The urinary G6PD activity and its association with the clinical markers were analyzed. Multivariate linear regression analysis was used to analyze the risk factors of urinary G6PD in these patients. Then, microRNAs that were differentially expressed in urine and could bind and degrade G6PD were screened and verified in patients with DKD. After that, high glucose (HG)-cultured human kidney cells (HK-2) and Zucker diabetic fatty (ZDF) rats were used to test the roles of miR-7977/G6PD/albumin-induced autophagy in DKD. Beclin and P62 were used as markers of kidney autophagy indicators. A dual-luciferase reporter assay system was used to test the binding of G6PD by mir-7977. The plasma and urinary G6PD activity were decreased significantly in patients with DKD, accompanied by increased urinary mir-7977 level. The fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and urinary albumin excretion were independent predictors of urinary G6PD activity, according to multiple linear regression analysis. The increased expression of miR-7977 and decreased expression of G6PD were also found in the kidney of ZDF rats with early renal tubular damage. The correlation analysis showed that beclin protein expression levels were positively correlated with kidney G6PD activity, whereas P62 protein expression was negatively correlated with kidney G6PD activity in rats. In HK-2 cells cultured with normal situation, a low level of albumin could induce autophagy along with the stimulation of G6PD, although this was impaired under high glucose. Overexpression of G6PD reversed albumin-induced autophagy in HK-2 cells under high glucose. Further study revealed that G6PD was a downstream target of miR-7977. Inhibition of miR-7977 expression led to significantly increased expression of G6PD and reversed the effects of high glucose on albumin-induced autophagy. In conclusion, our study supports a new mechanism of G6PD downregulation in DKD. Therapeutic measures targeting the miR-7977/G6PD/autophagy signaling pathway may help in the prevention and treatment of DKD. NEW & NOTEWORTHY: This study provides new evidence that reduced glucose-6-phosphate dehydrogenase (G6PD) may damage the endocytosis of renal tubular epithelial cells by reducing albumin-induced autophagy. More importantly, for the first time, our study has provided evidence from humans that the decrease in urinary G6PD activity is positively associated with renal injury, and abnormal glucose and lipid metabolism may be important reasons for reduced G6PD levels. Increased miR-7977 may at least in part explain the downregulation of G6PD. [ABSTRACT FROM AUTHOR]

Abstract Background Mutation of MMACHC gene causes cobalamin C disease (cblC), an inherited metabolic disorder, which presents as combined methylmalonic aciduria (MMA-uria) and hyperhomocysteinaemia in clinical. Renal complications may also be present in patients with this inborn deficiency. The most common histological change is thrombotic microangiopathy (TMA). However, to our acknowledge, renal tubular injury in the late-onset presentation of cblC is rarely been reported. This study provides a detailed description of the characteristics of kidney disease in cblC deficiency, aiming to improve the early recognition of this treatable disease for clinical nephrologists. Case presentation Here we described three teenage patients who presented with hematuria, proteinuria, and hypertension in clinical presentation. They were diagnosed with renal involvement due to cblC deficiency after laboratory tests revealing elevated serum and urine homocysteine, renal biopsy showing TMA and tubular injury, along with genetic testing showing heterogeneous compound mutations in MMACHC. Hydroxocobalamin, betaine, and L-carnitine were administered to these patients. All of them got improved, with decreased homocysteine, controlled blood pressure, and kidney outcomes recovered. Conclusions The clinical diagnosis of cblC disease associated with kidney injury should be considered in patients with unclear TMA accompanied by a high concentration of serum homocysteine, even in teenagers or adults. Early diagnosis and timely intervention are vital to improving the prognosis of cobalamin C disease. Clinical Trial Number Not applicable.

Introduction: Drug-induced tubulointerstitial injury is a common cause of renal impairment. Since the mechanisms of drug-induced tubular injury are diverse, various treatment approaches are needed according to the pathogenesis. Renal biopsy is indispensable to determine not only the pathological diagnosis, but also the underlying mechanism, and to guide appropriate treatment. Most recently, one of the red yeast supplements has been widely highlighted as a novel cause of tubular damage, mainly in Japan and Asia. However, neither detailed pathological findings nor the mechanism of renal impairment has been sufficiently reported. Case Presentation: Two cases of renal impairment after taking red yeast supplement internally are presented. Both cases showed renal dysfunction with low uric acid, potassium, and phosphorus levels, characteristic features of Fanconi syndrome. The renal biopsy findings of both cases showed severe injury to the proximal tubules with mild inflammatory cell infiltration. The proximal tubules exhibited diffuse loss of the brush border, flattening, and tubular lumen dilation. Immunofluorescence showed no deposition of immunoglobulin and complement in the glomeruli and tubules. Electron microscopic findings indicated proximal tubular damage without crystal deposition. Moreover, immunohistochemistry using the proximal tubular marker CD10 and a marker for distal tubules including the loop of Henle, E-cadherin, collectively demonstrated that the focus of renal injury in both cases was mainly the proximal tubules. Conclusions: The red yeast rice supplement itself, its metabolized product, or other unknown contaminant components might directly induce proximal tubulopathy rather than an allergic reaction-related tubulointerstitial nephritis.

Dual immunoglobulin domain-containing cell adhesion molecule (DICAM) is a type I transmembrane protein that presents in various cells including renal tubular cells. This study evaluated the expression and protective role of DICAM in renal tubular cell injury. HK-2 cells were incubated and treated with lipopolysaccharide (LPS, 30 μg/mL) or hydrogen peroxide (H2O2, 100 μM) for 24 h. To investigate the effect of the gene silencing of DICAM, small interfering RNA of DICAM was used. Additionally, to explain its role in cellular response to injury, DICAM was overexpressed using an adenoviral vector. DICAM protein expression levels significantly increased following treatment with LPS or H2O2 in HK-2 cells. In response to oxidative stress, DICAM showed an earlier increase (2–4 h following treatment) than neutrophil gelatinase-associated lipocalin (NGAL) (24 h following treatment). DICAM gene silencing increased the protein expression of inflammation-related markers, including IL-1β, TNF-α, NOX4, integrin β1, and integrin β3, in H2O2-induced HK-2 cell injury. Likewise, in the LPS-induced HK-2 cell injury, DICAM knockdown led to a decrease in occludin levels and an increase in integrin β3, IL-1β, and IL-6 levels. Furthermore, DICAM overexpression followed by LPS-induced HK-2 cell injury resulted in an increase in occludin levels and a decrease in integrin β1, integrin β3, TNF-α, IL-1β, and IL-6 levels, suggesting an alleviating effect on inflammatory responses. DICAM was elevated in the early stage of regular tubular cell injury and may protect against renal tubular injury through its anti-inflammatory properties. DICAM has a potential as an early diagnostic marker and therapeutic target for renal cell injury.

Objectives: The aim of this study was to investigate the mechanism of itaconate’s potential effect in diabetic kidney disease.Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy.Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions.Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

Rui Xue,1,&ast; Haiting Xiao,2,&ast; Vinod Kumar,3 Xiqian Lan,2 Ashwani Malhotra,4 Pravin C Singhal,4 Jianning Chen1 1Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China; 2Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 3Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India; 4Feinstein Institute for Medical Research and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA&ast;These authors contributed equally to this workCorrespondence: Jianning Chen; Pravin C Singhal, Email chenjn1987@zju.edu.cn; psinghal@northwell.eduAbstract: Diabetic nephropathy (DN) is a common complication affecting many diabetic patients, leading to end-stage renal disease. However, its pathogenesis still needs to be fully understood to enhance the effectiveness of treatment methods. Traditional theories are predominantly centered on glomerular injuries and need more explicit explanations of recent clinical observations suggesting that renal tubules equally contribute to renal function and that tubular lesions are early features of DN, even occurring before glomerular lesions. Although the conventional view is that DN is not an inflammatory disease, recent studies indicate that systemic and local inflammation, including tubulointerstitial inflammation, contributes to the development of DN. In patients with DN, intrinsic tubulointerstitial cells produce many proinflammatory factors, leading to medullary inflammatory cell infiltration and activation of inflammatory cells in the interstitial region. Therefore, understanding the molecular mechanism of renal tubulointerstitial inflammation contributing to DN injury is of great significance and will help further identify key factors regulating renal tubulointerstitial inflammation in the high glucose environment. This will aid in developing new targets for DN diagnosis and treatment and expanding new DN treatment methods.Keywords: diabetic nephropathy, renal tubules, renal tubular injury, renal tubulointerstitial inflammation, DN injury

Objective To explore the advantages of urinary matrix metalloproteinase-7 (MMP-7) in evaluating renal tubular injury in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) patients compared with urinary cystatin C (CysC) and retinol-binding protein (RBP). Methods Serum and urine samples were collected from 20 healthy volunteers, and 40 MCD and 20 FSGS patients. Serum and urinary MMP-7 levels were measured by enzyme-linked immunosorbent assay. Urinary total protein, CysC and RBP levels were measured by automatic specific protein analyzer and compared with urinary creatinine level for calibration. The renal tissue serial sections were stained by MMP-7 immunohistochemistry and periodic acid–Schiff. Results Under light microscopy, MMP-7 granular weak positive expression was showed sporadically in the cytoplasm of a few renal tubular epithelial cells without obvious morphological changes in MCD patients, and MMP-7-positive expression was observed in the cytoplasm of some renal tubular epithelial cells in FSGS patients. There was no significant difference in serum MMP-7 level among the three groups. Compared with the control group, the urinary MMP-7 level in MCD patients was higher, but urinary CysC and RBP levels were not increased significantly. Compared with the control group and MCD patients, urinary MMP-7, CysC and RBP levels in FSGS patients were upregulated significantly. Conclusions Urinary MMP-7 could not only evaluate the mild renal tubular epithelial cells injury in MCD patients with massive proteinuria, but also evaluate the continuous renal tubular epithelial cells injury in FSGS patients. [ABSTRACT FROM AUTHOR]

Aim: Irrespective of the cause, albumin/proteinuria induces tubulointerstitial damage and accelerates the progression of kidney diseases. Our series of studies demonstrated that proteinuria, an independent prognostic factor for chronic kidney disease (CKD), is correlated with urinary basigin/CD147 (Bsg) levels. We examined the morphology and origin of Bsg in the tubular lumen through the effects of filtered glucose and protein solutes on the tubules. Methods: Diabetic kidney disease (DKD) patients (N = 50) were treated with spironolactone 25 mg for 4 weeks or by conservative treatment. The associations between urinary Bsg values and clinical indicators were examined. Primary‐cultured proximal tubular epithelial cells (PTECs) from human adult kidneys were exposed to high glucose or bovine serum albumin (BSA). Results: In patients with early phase DKD, urinary Bsg levels were closely correlated with proteinuria but not HbA1c. Full‐length Bsg on extracellular vesicles (EVs) was investigated primarily in urine collected from DKD patients. EVs obtained from the urine of DKD patients included Bsg and SGLT2 proteins. Notably, spironolactone treatment concomitantly suppressed the release of Bsg‐bearing EVs in correlation with decreased albuminuria. Exposure of PTECs to BSA (but not high glucose) enhanced the storage of supernatant Bsg in EVs despite the absence of exposure‐specific changes in Bsg transcription. Conclusion: Proteinuria induces the release of Bsg‐bearing EVs derived from PTECs into the tubular lumen. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes and is a chronic progressive condition. It is also a common cause of end-stage renal disease (ESRD), which is characterized by proteinuria or a progressive decline in the glomerular filtration rate. Due to their dependence on high-energy and aerobic metabolism, renal tubules are more susceptible to the metabolic disturbances associated with DKD, leading to inflammation and fibrosis. Consequently, tubular injury has become a recent research focus, and significant advancements have been made in studying the role of extracellular vesicles in DKD-associated tubular injury. This review aimed to elucidate the mechanisms and potential applications of different types of extracellular vesicles in tubular injury in DKD to provide new insights for the prevention and treatment of DKD. [ABSTRACT FROM AUTHOR]

Fine particulate matter (PM2.5)-related health issues have received increasing attention as a worldwide public health problem, and PM2.5-related chronic kidney disease (CKD) has been emerging over the years. Limited research has focused on the mechanism of PM2.5-induced kidney disease. To investigate the impact of PM2.5 on the kidney and its potential mechanism, we generated a PM2.5-exposed C57BL/6 mouse model by using Shanghai Meteorological and Environment Animal Exposure System (Shanghai-METAS) for 12 weeks, urine, blood and kidney tissues were collected. The pathological changes and the function of the kidney were measured after PM2.5 exposure for 12 weeks. Along with glomerular damage, tubular damage was also severe in PM2.5-induced mice. The results of mRNA-seq indicate that pyroptosis is involved. Pyroptosis is defined as caspase-1-dependent programmed cell death in response to insults. The expression of the nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), Caspase-1, gasdermin D (GSDMD) and IL-1β was detected. NLRP3 inflammasome activation and subsequent pyroptosis were observed in PM2.5-exposed kidney tissues and PM2.5-exposed Bumpt cells too. At the meantime, the inhibitors of NLRP3 and caspase-1 were applied to the PM2.5 exposed Bumpt cells. It turned out to have a significant rescue effect of the inhibitors. This study revealed new insights into PM2.5-induced kidney injury and specific kidney pathological damage, as well as morphological changes, and defined the important role of pyroptosis in PM2.5-induced kidney dysfunction.

Chronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. We conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-β- d -glucosaminidase (NAG). In patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). Our results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease. • Intermittent hypoxia plays an important role in the pathogenesis of OSA. • Urinary NAG was elevated as their 3% oxygen desaturation index increased. • Elevated urinary NAG decreased following CPAP treatment in patients with OSA. • OSA patients may be susceptible to renal tubular damage. [ABSTRACT FROM AUTHOR]

Ran Li,1 Dunmin She,2 Zhengqin Ye,1 Ping Fang,1 Guannan Zong,1 Yong Zhao,1 Kerong Hu,1 Liya Zhang,1 Sha Lei,1 Keqin Zhang,1 Ying Xue1 1Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China; 2Department of Endocrinology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, 225001, People’s Republic of ChinaCorrespondence: Ying Xue; Keqin Zhang, Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, No. 389, Xincun Road, Shanghai, 200065, People’s Republic of China, Tel +86-021-66111061, Email doxy0622@163.com; keqzhang2018@163.comPurpose: This study aims to investigate the renal protective effect of glucagon-like peptide 1 receptor agonist (GLP-1RA) on improving renal tubular damage in diabetic kidney disease (DKD) and to explore the potential mechanism of GLP-1RA on renal tubular protection.Methods: Long-acting GLP-1RA was used to treat DKD mice for 12 weeks. The label-free quantitative proteomic analysis of renal proteins was conducted to explore the differentially expressed proteins (DEPs) in the renal tissues of the control, DKD and GLP-1RA groups. The DEPs and markers of renal tubular injury were verified by qPCR in vivo and in vitro. The expression of glucagon-likepeptide-1 receptor (GLP-1R) in renal tubules was determined by immunofluorescence staining.Results: GLP-1RA treatment significantly improved the tubular damages in kidney tissues of DKD mice and mTEC cells stimulated by high glucose (HG). Proteomics analysis revealed that 30 proteins in kidney tissue were differentially expressed among three groups. Seminal vesicle secretory protein 6 (SVS6) was the most differentially expressed protein in kidney tissues among three groups of mice. The expression changes of Svs6 mRNA in vitro and in vivo detected by qPCR were consistent with the results of proteomic analysis. Furthermore, reduction of Svs6 expression by SVS6 siRNA could attenuate HG-stimulated tubular injury in mTEC cells. Immunofluorescence staining also found that GLP-1R was widely expressed in renal tubules in vitro and in vivo.Conclusion: GLP-1RA significantly improved renal tubular damage in DKD mice. SVS6 may be a potential therapeutic target for GLP-1RA in the treatment of DKD.Keywords: diabetic kidney disease, glucagon-like peptide-1 receptor agonist, renal tubular injury, seminal vesicle secretory protein 6

Background: Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical. Methods: This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis. Results: The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A. Conclusions: For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis. [ABSTRACT FROM AUTHOR]

The intricate processes that govern the interactions between peripatetic immune cells and distal renal injury in obesity are not fully understood. Employing transcriptomic analysis of circulating extracellular vesicles (EVs), a marked amplification of small RNA (miR-3960) is discerned within CD3 - CD19 + B cells. This RNA is found to be preferentially augmented in kidney tissues, contrasting with its subdued expression in other organs. By synthesizing dual-luciferase reporter assay with co-immunoprecipitation analysis, it is pinpointed that miR-3960 specifically targets the nuclear gene TRMT5, a pivotal actor in the methylation of mitochondrial tRNA. This liaison instigates aberrations in the post-transcriptional modifications of mitochondrial tRNA, engendering deficiencies within the electron respiratory chain, primarily attributable to the diminution of the mitochondrial bioenergetic compound (NDUFA7) complex I. Such perturbations lead to a compromised mitochondrial respiratory capacity in renal tubular cells, thereby exacerbating tubular injury. In contrast, EV blockade or miR-3960 depletion markedly alleviates renal tubular injury in obesity. This investigation unveils a hitherto unexplored pathway by which obesity-induced circulating immune cells remotely manipulate mitochondrial metabolism in target organs. The strategic targeting of obese EVs or infiltrative immune cells and their specifically secreted RNAs emerges as a promising therapeutic avenue to forestall obesity-related renal afflictions., (© 2024 Wiley‐VCH GmbH.)

Diabetic nephropathy (DN) causes serious renal tubule and interstitial damage, but effective prevention and treatment measures are lacking. Abnormal mitophagy may be involved in the progression of DN, but its upstream and downstream regulatory mechanisms remain unclear. Melatonin, a pineal hormone associated with circadian rhythms, is involved in regulating mitochondrial homeostasis. Here, we demonstrated abnormal mitophagy in the kidneys of DN mice or high glucose (HG)-treated HK-2 cells, which was accompanied by increased oxidative stress and inflammation. At the same time, the melatonin treatment alleviated kidney damage. After mitochondrial isolation, we found that melatonin promoted AMPK phosphorylation and accelerated the translocation of PINK1 and Parkin to the mitochondria, thereby activating mitophagy, reducing oxidative stress, and inhibiting inflammation. Interestingly, the renal protective effect of melatonin can be partially blocked by downregulation of PINK1 and inhibition of AMPK. Our studies demonstrated for the first time that melatonin plays a protective role in DN through the AMPK-PINK1-mitophagy pathway.

Background: Diabetic nephropathy (DN) is a serious complication among patients with diabetes. Elucidating its pathogenesis is crucial for identifying novel biomarkers and therapeutic targets for DN. Methods: DN tissues were harvested for examining MALAT1, LIN28A and Nox4. Human kidney-2 (HK-2) cells were treated with high glucose (HG) for establishing a cell model of DN. Cell viability was examined by MTT assay. HG-induced cell apoptosis and secretion of TNF-α and IL-6 were analyzed by TUNEL and ELISA assays, respectively. RIP and RNA pull-down assays were applied to analyze the interaction between MALAT1, LIN28A and Nox4 in HK-2 and human embryonic kidney 293T (HEK-293T) cells. A rat model of DN was established to determine the role of MALAT1 in DN in vivo. Results: MALAT1, LIN28A and Nox4 were upregulated in DN tissues and HG-treated HK-2 cells. Overexpression of MALAT1, LIN28A or Nox4 reduced cell viability and enhanced cell apoptosis, ROS generation and secretion of inflammatory cytokines in HG-treated HK-2 cells, whereas knockdown of MALAT1, LIN28A or Nox4 exerted opposite effects. Furthermore, MALAT1 directly interacted with LIN28A. Moreover, MALAT1 facilitated the interaction between LIN28A and Nox4 to increase Nox4 stability. Knockdown of Nox4 relieved HG-induced injury by suppressing the AMPK/mTOR signaling in HK-2 cells. Knockdown of MALAT1 alleviated renal tubular epithelial injury by suppressing LIN28A and the Nox4/AMPK/TOR signaling in DN. Conclusion: MALAT1 activates the AMPK/mTOR signaling via interacting with LIN28A to stabilize Nox4 mRNA, thereby aggravating high glucose-induced renal tubular epithelial injury. Our findings provide potential therapeutic targets for DN. [ABSTRACT FROM AUTHOR]

Renal tubular injury induced by free fatty acid bound to albumin is the key pathological basis for the progression of diabetic kidney disease. However, effective interventions are limited. Astragaloside IV, as a major bioactive component purified from Astragalus membranaceus (Fisch.) Bunge, possesses pharmacological properties of lowering blood glucose and proteinuria, and renal tubular protection in diabetic kidney disease. Further work is needed to understand the underlying molecular mechanisms. This study was designed to investigate the mechanism of renal tubular protection by astragaloside IV in diabetic kidney disease. Rats receiving high-fat diet combined with streptozotocin (30 mg/kg, i.p.) were gavaged with astragaloside IV (10 mg/kg/d or 20 mg/kg/d) or empagliflozin (1.72 mg/kg/d) for 8 weeks. In vitro , the NRK-52E cells were treated with free fatty acid-deleted BSA or palmitic acid-bound BSA in the presence or absence of astragaloside IV (5 μM, 10 μM, 20 μM) or 5 μM of mcc950. The effects of astragaloside IV on mitochondrial function, NLRP3/ASC/IL-18/IL-1β inflammatory cascade, and renal tubular injury were detected by pathological staining, immunoblotting, MitoSOX Red staining. Next, to investigate the mechanism of renal tubular protection by astragaloside IV, we transfected Fatp2 siRNA into BSA-PA-treated NRK-52E cells and injected lipofermata (a FATP2 inhibitor) intraperitoneally into free fatty acid-bound BSA overloaded rats with concomitant astragaloside IV treatment. Treatment with astragaloside IV for 8 weeks dose-dependently attenuated the blood glucose, ratio of urinary albumin to creatinine, disorder of lipid metabolism, and pathological injury in diabetic kidney disease rats. In addition, astragaloside IV dose-dependently attenuated mitochondrial-derived reactive oxygen species and subsequent inhibiting NLRP3-mediated inflammatory cascade in diabetic kidney disease rats and palmitic acid-bound BSA-treated NRK-52E cells, thereby exerting renal tubular protection. More importantly, the effects of astragaloside IV on restoration of mitochondrial function, inhibition of inflammatory response and amelioration of renal tubular injury in vivo and in vitro were further enhanced when used in combination with Fatp2 siRNA or lipofermata. Astragaloside IV exerts antioxidant and anti-inflammatory effects in diabetic kidney disease by inhibiting FATP2-mediated fatty acid transport, thereby attenuating renal tubular injury. [Display omitted] [ABSTRACT FROM AUTHOR]

BackgroundDiabetic nephropathy (DN) is a serious complication among patients with diabetes. Elucidating its pathogenesis is crucial for identifying novel biomarkers and therapeutic targets for DN.MethodsDN tissues were harvested for examining MALAT1, LIN28A and Nox4. Human kidney-2 (HK-2) cells were treated with high glucose (HG) for establishing a cell model of DN. Cell viability was examined by MTT assay. HG-induced cell apoptosis and secretion of TNF-α and IL-6 were analyzed by TUNEL and ELISA assays, respectively. RIP and RNA pull-down assays were applied to analyze the interaction between MALAT1, LIN28A and Nox4 in HK-2 and human embryonic kidney 293T (HEK-293T) cells. A rat model of DN was established to determine the role of MALAT1 in DN in vivo.ResultsMALAT1, LIN28A and Nox4 were upregulated in DN tissues and HG-treated HK-2 cells. Overexpression of MALAT1, LIN28A or Nox4 reduced cell viability and enhanced cell apoptosis, ROS generation and secretion of inflammatory cytokines in HG-treated HK-2 cells, whereas knockdown of MALAT1, LIN28A or Nox4 exerted opposite effects. Furthermore, MALAT1 directly interacted with LIN28A. Moreover, MALAT1 facilitated the interaction between LIN28A and Nox4 to increase Nox4 stability. Knockdown of Nox4 relieved HG-induced injury by suppressing the AMPK/mTOR signaling in HK-2 cells. Knockdown of MALAT1 alleviated renal tubular epithelial injury by suppressing LIN28A and the Nox4/AMPK/TOR signaling in DN.ConclusionMALAT1 activates the AMPK/mTOR signaling via interacting with LIN28A to stabilize Nox4 mRNA, thereby aggravating high glucose-induced renal tubular epithelial injury. Our findings provide potential therapeutic targets for DN.

Acute kidney injury (AKI) is a substantial worldwide public health concern with no specific and effective therapies in clinic. NAD+ is a pivotal determinant of cellular energy metabolism involved in the progression of AKI; however, its mechanism in kidney injury remains poorly understood. Sirtuin 1 (SIRT1) is an NAD+‐dependent deacetylase associated with renal protection and acute stress resistance. In this study, we have investigated the role of NAD+ in AKI and the potential mechanism(s) involved in its renoprotective effect. NAD+ was notably decreased and negatively correlated with kidney dysfunction in AKI, restoring NAD+ with NMN significantly ameliorates LPS‐induced oxidative stress and apoptosis and attenuates renal damage. We also found that the protection of NAD+ is associated with SIRT1 expressions and performs in a SIRT1‐dependent manner. Inhibition of SIRT1 blunted the protective effect of NAD+ and up‐regulated the activity of glycogen synthase kinase‐3β (GSK‐3β) that was concomitant with mitigated Nrf2 nuclear accumulation, thereby exacerbates AKI. These findings suggest that NAD+/SIRT1/GSK‐3β/Nrf2 axis is an important mechanism that can protect against AKI which might be a potential therapeutic target for the treatment of AKI. [ABSTRACT FROM AUTHOR]

Objects This study aimed to analyze the clinicopathological features of acute kidney disease (AKD) with renal oxalosis. Methods Data for biopsy-proven AKD with oxalosis diagnosed from Jan 2011 to Oct 2018 was collected. The underlying diseases, dietary habits, clinical and pathological characteristics of newly emerging kidney disease were analyzed. The long-term renal prognosis was observed. Results A total of 23 patients were included, comprised of 18 men and 5 women with a mean age of 51.6 ± 15.9 years. The peak Scr was 669.9 ± 299.8 μmol/L, and 95.7% of patients had stage 3 acute kidney injury (AKI). Drug-induced tubulointerstitial nephritis (TIN) was the most common cause (65.2%) of AKD, followed by severe nephrotic syndrome (17.4%). All patients had pathological changes indicating TIN, and 11 patients were complicated with the newly emerging glomerular disease (GD). The risk of oxalosis caused by increased enterogenous oxalate absorption accounted for only 26.1%, and others came from new kidney diseases. The majority (75%) of abundant (medium to severe) oxalosis occurred in patients without GD. There were no significant differences in the score for tubular injury (T-IS) and interstitial inflammation with different severities of oxalosis. Rate of Scr decrease (ΔScr%) at 2 weeks was negatively correlated with the severity of oxalosis (R = −0.542, p = 0.037), score for T-IS (R = −0.553, p = 0.033), and age (R = −0.736, p = 0.002). The decrease in Scr at 4 weeks was correlated with T-IS (R = −0.433), but had no correlation with oxalosis. Conclusions The present findings revealed that 95.7% of AKD with secondary renal oxalosis occurred in critically ill patients. AKD from tubular injury was the prominent cause. Severe oxalosis contributed to delayed early recovery of AKD.

Objectives: The aim of this study was to investigate the mechanism of itaconate's potential effect in diabetic kidney disease., Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy., Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro ; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions., Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

This study aimed to analyze the clinicopathological features of acute kidney disease (AKD) with renal oxalosis. Data for biopsy-proven AKD with oxalosis diagnosed from Jan 2011 to Oct 2018 was collected. The underlying diseases, dietary habits, clinical and pathological characteristics of newly emerging kidney disease were analyzed. The long-term renal prognosis was observed. A total of 23 patients were included, comprised of 18 men and 5 women with a mean age of 51.6 ± 15.9 years. The peak Scr was 669.9 ± 299.8 μmol/L, and 95.7% of patients had stage 3 acute kidney injury (AKI). Drug-induced tubulointerstitial nephritis (TIN) was the most common cause (65.2%) of AKD, followed by severe nephrotic syndrome (17.4%). All patients had pathological changes indicating TIN, and 11 patients were complicated with the newly emerging glomerular disease (GD). The risk of oxalosis caused by increased enterogenous oxalate absorption accounted for only 26.1%, and others came from new kidney diseases. The majority (75%) of abundant (medium to severe) oxalosis occurred in patients without GD. There were no significant differences in the score for tubular injury (T-IS) and interstitial inflammation with different severities of oxalosis. Rate of Scr decrease (ΔScr%) at 2 weeks was negatively correlated with the severity of oxalosis (R = −0.542, p = 0.037), score for T-IS (R = −0.553, p = 0.033), and age (R = −0.736, p = 0.002). The decrease in Scr at 4 weeks was correlated with T-IS (R = −0.433), but had no correlation with oxalosis. The present findings revealed that 95.7% of AKD with secondary renal oxalosis occurred in critically ill patients. AKD from tubular injury was the prominent cause. Severe oxalosis contributed to delayed early recovery of AKD. [ABSTRACT FROM AUTHOR]

Introduction: Drug-induced tubulointerstitial injury is a common cause of renal impairment. Since the mechanisms of drug-induced tubular injury are diverse, various treatment approaches are needed according to the pathogenesis. Renal biopsy is indispensable to determine not only the pathological diagnosis, but also the underlying mechanism, and to guide appropriate treatment. Most recently, one of the red yeast supplements has been widely highlighted as a novel cause of tubular damage, mainly in Japan and Asia. However, neither detailed pathological findings nor the mechanism of renal impairment has been sufficiently reported., Case Presentation: Two cases of renal impairment after taking red yeast supplement internally are presented. Both cases showed renal dysfunction with low uric acid, potassium, and phosphorus levels, characteristic features of Fanconi syndrome. The renal biopsy findings of both cases showed severe injury to the proximal tubules with mild inflammatory cell infiltration. The proximal tubules exhibited diffuse loss of the brush border, flattening, and tubular lumen dilation. Immunofluorescence showed no deposition of immunoglobulin and complement in the glomeruli and tubules. Electron microscopic findings indicated proximal tubular damage without crystal deposition. Moreover, immunohistochemistry using the proximal tubular marker CD10 and a marker for distal tubules including the loop of Henle, E-cadherin, collectively demonstrated that the focus of renal injury in both cases was mainly the proximal tubules., Conclusions: The red yeast rice supplement itself, its metabolized product, or other unknown contaminant components might directly induce proximal tubulopathy rather than an allergic reaction-related tubulointerstitial nephritis., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The long-term impact of COVID-19 on transplant recipients remains unknown. We describe the case of a 30-year-old male kidney transplant recipient from Wuhan, China that was treated for severe COVID-19 in February 2020. He suffered an acute lung and renal injury and required systemic treatment including adjustment of his immunosuppressant regime. He was followed up to 1-year after discharge. No chronic lung fibrosis or deterioration of his pulmonary function was observed. Despite COVID-19 mediated damage to his renal tubular cells, no transplant rejection occurred. His immunological profile demonstrated both cellular anti-SARS-CoV-2 reactivity and specific humoral immunity, indicating that it is beneficial for the transplanted patients to be immunized with SARS-CoV-2 virus vaccine. This case will help guide clinical decision making for immunocompromised individuals that become infected with SARS-CoV-2. [ABSTRACT FROM AUTHOR]

BackgroundChronic kidney disease is common and is associated with increased cardiovascular disease risk. Currently, markers of renal tubular injury are not used routinely to describe kidney health and little is known about the risk of cardiovascular events and death associated with these biomarkers independent of glomerular filtration-based markers (such as serum creatinine or albuminuria).Study designCohort study, CRIC (Chronic Renal Insufficiency Cohort) Study.Setting & participants3,386 participants with estimated glomerular filtration rate of 20 to 70mL/min/1.73m(2) enrolled from June 2003 through August 2008.PredictorUrine neutrophil gelatinase-associated lipocalin (NGAL) concentration.OutcomesAdjudicated heart failure event, ischemic atherosclerotic event (myocardial infarction, ischemic stroke, or peripheral artery disease), and death through March 2011.MeasurementsUrine NGAL measured at baseline with a 2-step assay using chemiluminescent microparticle immunoassay technology on an ARCHITECT i2000SR (Abbott Laboratories).ResultsThere were 428 heart failure events (during 16,383 person-years of follow-up), 361 ischemic atherosclerotic events (during 16,584 person-years of follow-up), and 522 deaths (during 18,214 person-years of follow-up). In Cox regression models adjusted for estimated glomerular filtration rate, albuminuria, demographics, traditional cardiovascular disease risk factors, and cardiac medications, higher urine NGAL levels remained associated independently with ischemic atherosclerotic events (adjusted HR for the highest [>49.5ng/mL] vs lowest [≤6.9ng/mL] quintile, 1.83 [95% CI, 1.20-2.81]; HR per 0.1-unit increase in log urine NGAL, 1.012 [95% CI, 1.001-1.023]), but not heart failure events or deaths.LimitationsUrine NGAL was measured only once.ConclusionsAmong patients with chronic kidney disease, urine levels of NGAL, a marker of renal tubular injury, were associated independently with future ischemic atherosclerotic events, but not with heart failure events or deaths.

The long-term impact of COVID-19 on transplant recipients remains unknown. We describe the case of a 30-year-old male kidney transplant recipient from Wuhan, China that was treated for severe COVID-19 in February 2020. He suffered an acute lung and renal injury and required systemic treatment including adjustment of his immunosuppressant regime. He was followed up to 1-year after discharge. No chronic lung fibrosis or deterioration of his pulmonary function was observed. Despite COVID-19 mediated damage to his renal tubular cells, no transplant rejection occurred. His immunological profile demonstrated both cellular anti-SARS-CoV-2 reactivity and specific humoral immunity, indicating that it is beneficial for the transplanted patients to be immunized with SARS-CoV-2 virus vaccine. This case will help guide clinical decision making for immunocompromised individuals that become infected with SARS-CoV-2.

New Findings: What is the central question of this study?Diabetic nephropathy (DN) is a severe complication of diabetes correlated with a higher mortality rate in diabetic patients. Renal tubular injury participates in the pathogenesis of DN. We aimed to uncover the biological function of the NEAT1–miR‐150‐5p–DRP1 axis in an in vitro model of DN and elaborate the potential mechanisms.What is the main finding and its importance?NEAT1 facilitated high glucose‐induced damage in HK‐2 cells by reducing mitophagy via the miR‐150‐5p–DRP1 axis, which sheds light on DN pathogenesis and reveals a potential treatment for DN. Diabetic nephropathy (DN) is a severe complication in diabetic patients, with a high mortality rate. Renal tubular injury is involved in the pathogenesis of DN. In this study, we aimed to uncover the regulatory roles of the NEAT1–miR‐150‐5p–DRP1 axis in an in vitro model of DN and its possible mechanisms. High glucose‐challenged HK‐2 cells were used as an in vitro DN model. NEAT1, miR‐150‐5p and DRP1 levels were assessed by RT‐qPCR. Cell viability was determined by the MTT assay. MitoSOX Red and JC‐1 were used to evaluate intracellular production of reactive oxygen species and mitochondrial membrane potential, respectively. Lactate dehydrogenase release and superoxide dismutase activity were assessed with commercial kits. The protein levels of DRP1, p62, BECN1(beclin 1) and BNIP3 were determined by western blotting. The interaction between NEAT1 (DRP1) and miR‐150‐5p was verified by a dual‐luciferase reporter assay and an RNA immunoprecipitation assay. Our results showed that in response to high glucose the NEAT1 and DRP1 levels were upregulated, whereas the miR‐150‐5p level was downregulated in HK‐2 cells. Knockdown of NEAT1 or DRP1 in high glucose‐challenged HK‐2 cells inhibited excessive reactive oxygen species production and lactate dehydrogenase release, increased cell viability, mitochondrial membrane potential and superoxide dismutase activity and enhanced mitophagy. Inhibition of miR‐150‐5p resulted in the opposite results. Mechanistically, NEAT1 sponged miR‐150‐5p to increase the DRP1 level. Moreover, silencing of NEAT1 or DRP1 could counteract miR‐150‐5p inhibition‐induced deleterious effects. Collectively, our findings indicate that NEAT1 facilitates high glucose‐induced damage in HK‐2 cells by suppressing mitophagy via the miR‐150‐5p–DRP 1 axis, which sheds light on a novel mechanism of DN. [ABSTRACT FROM AUTHOR]

Introduction Microalbuminuria is considered an early marker of glomerular injury in patients with diabetes, but tubular injury can precede glomerular injury and cannot be detected by microalbumin. We need a new and early marker of kidney injury in normoalbuminuric diabetic patients. Urinary heme oxygenase-1 (uHO-1) is an enzyme that is produced in tubules in response to oxidative stress and can be a marker of tubular injury. Aim To investigate the clinical implication of uHO-1 as an early diagnostic marker in diabetic nephropathy (DN). Patients and methods A total of 65 diabetic patients, comprising 20 microalbuminuric patients and 45 normoalbuminuric patients, and 20 healthy participants as a control group were included in this study. Level of uHO-1 was detected by enzyme-linked immunosorbent assay. Results uHO-1 was highly significantly elevated (P

BackgroundFerroptosis is a recently identified iron-dependent form of cell death as a result of increased reactive oxygen species (ROS) and lipid peroxidation. In this study, we investigated whether ferroptosis aggravated diabetic nephropathy (DN) and damaged renal tubules through hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway in db/db mice.MethodsDb/db mice were administered with or without ferroptosis inhibitor Ferrostatin-1 treatment, and were compared with db/m mice.ResultsDb/db mice showed higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and Ferrostatin-1 reduced UACR in db/db mice. Db/db mice presented higher kidney injury molecular-1 and neutrophil gelatinase-associated lipocalin in kidneys and urine compared to db/m mice, with renal tubular basement membranes folding and faulting. However, these changes were ameliorated in db/db mice after Ferrostatin-1 treatment. Fibrosis area and collagen I were promoted in db/db mouse kidneys as compared to db/m mouse kidneys, which was alleviated by Ferrostatin-1 in db/db mouse kidneys. HIF-1α and HO-1 were increased in db/db mouse kidneys compared with db/m mouse kidneys, and Ferrostatin-1 decreased HIF-1α and HO-1 in db/db mouse kidneys. Iron content was elevated in db/db mouse renal tubules compared with db/m mouse renal tubules, and was relieved in renal tubules of db/db mice after Ferrostatin-1 treatment. Ferritin was increased in db/db mouse kidneys compared with db/m mouse kidneys, but Ferrostatin-1 reduced ferritin in kidneys of db/db mice. Diabetes accelerated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS formation in mouse kidneys, but Ferrostatin-1 prevented ROS formation derived by NADPH oxidases in db/db mouse kidneys. The increased malondialdehyde (MDA) and the decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px) were detected in db/db mouse kidneys compared to db/m mouse kidneys, whereas Ferrostatin-1 suppressed MDA and elevated SOD, CAT, and GSH-Px in db/db mouse kidneys. Glutathione peroxidase 4 was lower in db/db mouse kidneys than db/m mouse kidneys, and was exacerbated by Ferrostatin-1 in kidneys of db/db mice.ConclusionsOur study indicated that ferroptosis might enhance DN and damage renal tubules in diabetic models through HIF-1α/HO-1 pathway.

The number of patients with chronic kidney disease (CKD) is growing continuously globally. In order to study pathogenesis and mechanisms, many animal models have been developed, including spontaneous, genetic, and induced models. Although each type of CKD shows disease-specific tissue changes in the early stages, tubular disorder and interstitial fibrosis histologically occur in the course of progression to end-stage renal failure. Therefore, the quantification of tubular disorder and interstitial fibrosis in CKD research using animal models is essential for measuring the degree of CKD severity and, thus, efficacy of therapeutic agents. Several strategies have been used to quantify interstitial fibrosis. Among scoring factors, renal tubular flattening can be quantitatively evaluated easily and inexpensively. However, the diagnostic value of renal tubular flattening evaluation has not been investigated previously. Therefore, in this study, we investigated the correlation between renal tubular flattening and interstitial fibrosis or renal tubular injury markers. We observed a strong correlation between the degree of tubular injury/interstitial fibrosis and renal tubular flattening in three types of mouse renal disease model. This is advantageous because rapidly advancing technologies such as artificial intelligence and image processing can be easily applied; hence, a more precise, objective, and quantitative diagnosis should be possible in the future. [ABSTRACT FROM AUTHOR]

Background: Ferroptosis is a recently identified iron-dependent form of cell death as a result of increased reactive oxygen species (ROS) and lipid peroxidation. In this study, we investigated whether ferroptosis aggravated diabetic nephropathy (DN) and damaged renal tubules through hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway in db/db mice. Methods: Db/db mice were administered with or without ferroptosis inhibitor Ferrostatin-1 treatment, and were compared with db/m mice. Results: Db/db mice showed higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and Ferrostatin-1 reduced UACR in db/db mice. Db/db mice presented higher kidney injury molecular-1 and neutrophil gelatinase-associated lipocalin in kidneys and urine compared to db/m mice, with renal tubular basement membranes folding and faulting. However, these changes were ameliorated in db/db mice after Ferrostatin-1 treatment. Fibrosis area and collagen I were promoted in db/db mouse kidneys as compared to db/m mouse kidneys, which was alleviated by Ferrostatin-1 in db/db mouse kidneys. HIF-1α and HO-1 were increased in db/db mouse kidneys compared with db/m mouse kidneys, and Ferrostatin-1 decreased HIF-1α and HO-1 in db/db mouse kidneys. Iron content was elevated in db/db mouse renal tubules compared with db/m mouse renal tubules, and was relieved in renal tubules of db/db mice after Ferrostatin-1 treatment. Ferritin was increased in db/db mouse kidneys compared with db/m mouse kidneys, but Ferrostatin-1 reduced ferritin in kidneys of db/db mice. Diabetes accelerated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS formation in mouse kidneys, but Ferrostatin-1 prevented ROS formation derived by NADPH oxidases in db/db mouse kidneys. The increased malondialdehyde (MDA) and the decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px) were detected in db/db mouse kidneys compared to db/m mouse kidneys, whereas Ferrostatin-1 suppressed MDA and elevated SOD, CAT, and GSH-Px in db/db mouse kidneys. Glutathione peroxidase 4 was lower in db/db mouse kidneys than db/m mouse kidneys, and was exacerbated by Ferrostatin-1 in kidneys of db/db mice. Conclusions: Our study indicated that ferroptosis might enhance DN and damage renal tubules in diabetic models through HIF-1α/HO-1 pathway. [ABSTRACT FROM AUTHOR]

Background/Aims: Obesity-related kidney disease is associated with elevated levels of saturated free fatty acids (SFA). SFA lipotoxicity in tubular cells contributes to significant cellular apoptosis and injury. Salvianolic acid B (SalB) is the most abundant bioactive molecule from Radix Salviae Miltiorrhizae. In this study, we investigated the effect of SalB on SFA-induced renal tubular injury and endoplasmic reticulum (ER) stress, in vivo and in vitro.Methods: C57BL/6 mice were assigned to five groups: a control group with normal diet (Nor), high-fat diet group (HFD), and HFD with three different SalB treatment doses, low (SalBL; 3 mg/kg), medium (SalBM; 6.25 mg/kg), and high (SalBH; 12.5 mg/kg) doses. SalB was intraperitoneally injected daily for 4 weeks after 8 weeks of HFD. After 12 weeks, mice were sacrificed and kidneys and sera were collected. Apoptosis and ER stress were induced in human proximal tubule epitelial (HK2) cells by palmitic acid (PA, 0.6 mM), tunicamycin (TM, 1 μg/ml), or thapsigargin (TG, 200 nM) in vitro.Results: C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks exhibited increased apoptosis (Bax and cleaved caspase-3) and ER stress (BIP, P-eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1s) markers expression in the kidney, compared with control mice, which were remarkably suppressed by SalB treatment. In vitro studies showed that PA (0.6 mM) induced apoptosis and ER stress in cultured HK2 cells. SalB treatment attenuated all the adverse effects of PA. However, SalB failed to inhibit TM or TG-induced ER stress in HK2 cells.Conclusion: The study indicated that SalB may play an important role in obesity-related kidney injury via mediating SFA-induced ER stress.

C-X-C Motif Chemokine Ligand 6 (CXCL6) is an important chemokine. We attempt in this investigation to explore its role and possible mechanism in diabetic kidney disease (DKD). By intergrating GEO data, CXCL6 expression in DKD patients and normal controls was exhibited. miRWalk website and luciferase reporter assay were used to predict and verify the upstream miRNA of CXCL6. CCK-8 assay and flow cytometry were performed to detect proliferation and apoptosis capacities. The levels of inflammatory key factors (TNF-α, IL-6 and IL-8) were measured using ELISA analysis. Expression of CXCL6, miR-20a, and JAK/STAT3 pathway-related markers were detected by qRT-PCR or western blot assays. CXCL6 was increased in DKD. miR-20a was identified as an upstream regulatory miRNA of CXCL6, and its expression was decreased in DKD and HG-treated HK-2 cells. miR-20a overexpression facilitated the proliferation of HG-treated HK-2 cells, whereas miR-20a depletion exhibited the opposite phenomenon. The levels of TNF-α, IL-6 and IL-8 were increased by HG treatment in HK-2 cells. CXCL6 antagonized the promoting impacts of miR-20a mimics on HG-exposed HK-2 cell proliferation. The suppressive effect of miR-20a overexpression on apoptosis and inflammatory response of HG-induced HK-2 cell was rescued by CXCL6 enhancement. The protein expression of p-JAK and p-STAT3 were reduced by miR-20a mimic while facilitated by CXCL6 overexpression in HG-stimulated HK-2 cells. These consequences hinted that miR-20a might exert a repressive impact on DKD, possibly through targeting CXCL6 and mediating JAK/STAT3 pathway, which offer new targets for DKD treatment. [ABSTRACT FROM AUTHOR]

Dual immunoglobulin domain-containing cell adhesion molecule (DICAM) is a type I transmembrane protein that presents in various cells including renal tubular cells. This study evaluated the expression and protective role of DICAM in renal tubular cell injury. HK-2 cells were incubated and treated with lipopolysaccharide (LPS, 30 μg/mL) or hydrogen peroxide (H 2 O 2 , 100 μM) for 24 h. To investigate the effect of the gene silencing of DICAM, small interfering RNA of DICAM was used. Additionally, to explain its role in cellular response to injury, DICAM was overexpressed using an adenoviral vector. DICAM protein expression levels significantly increased following treatment with LPS or H 2 O 2 in HK-2 cells. In response to oxidative stress, DICAM showed an earlier increase (2-4 h following treatment) than neutrophil gelatinase-associated lipocalin (NGAL) (24 h following treatment). DICAM gene silencing increased the protein expression of inflammation-related markers, including IL-1β, TNF-α, NOX4, integrin β1, and integrin β3, in H 2 O 2 -induced HK-2 cell injury. Likewise, in the LPS-induced HK-2 cell injury, DICAM knockdown led to a decrease in occludin levels and an increase in integrin β3, IL-1β, and IL-6 levels. Furthermore, DICAM overexpression followed by LPS-induced HK-2 cell injury resulted in an increase in occludin levels and a decrease in integrin β1, integrin β3, TNF-α, IL-1β, and IL-6 levels, suggesting an alleviating effect on inflammatory responses. DICAM was elevated in the early stage of regular tubular cell injury and may protect against renal tubular injury through its anti-inflammatory properties. DICAM has a potential as an early diagnostic marker and therapeutic target for renal cell injury.

Growth arrest and DNA damage-inducible beta (GADD45B) is closely linked with cell cycle arrest, DNA repair, cell survival, or apoptosis in response to stress and is known to regulate the mitogen-activated protein kinase (MAPK) pathway. Here, using an RNA sequencing approach, we determined that GADD45B was significantly upregulated in diabetic kidneys, which was accompanied by renal tubular epithelial-mesenchymal transition (EMT) and apoptosis, as well as elevated MAPK pathway activation. In vitro, GADD45B expression in cultured human kidney proximal tubular epithelial cells (HK-2 cells) was also stimulated by high glucose (HG). In addition, overexpression of GADD45B in HK-2 cells exacerbated renal tubular EMT and apoptosis and increased p38 MAPK and c-Jun N-terminal kinases (JNK) activation, whereas knockdown of GADD45B reversed these changes. Notably, the activity of extracellular regulated kinase (ERK) was not affected by GADD45B expression. Furthermore, inhibitors of p38 MAPK (SB203580) and JNK (SP600125) alleviated HG‐ and GADD45B overexpression-induced renal tubular epithelial-mesenchymal transition and apoptosis. These findings indicate a role of GADD45B in diabetes-induced renal tubular EMT and apoptosis via the p38 MAPK and JNK pathways, which may be an important mechanism of diabetic kidney injury.

Acute kidney injury (AKI) is a common complication in cancer patients. Kidney function is closely related to patients’ quality of life and tumor prognosis. Cisplatin is a highly effective anti-tumor drug. However, the use of cisplatin is limited by its nephrotoxicity. It has been reported that FGF21 has a renal-protective function, but the mechanisms by which it does so remain unclear. In this study, we show that the expression of FGF21 is significantly upregulated in both in vitro and in vivo cisplatin-induced AKI models. Administration of recombinant FGF21 to cisplatin-induced AKI mice resulted in significantly decreased blood urea nitrogen (BUN) and serum creatinine levels, as well as significantly reduced protein levels of kidney injury molecule-1 (TIM-1), C-caspase 3, and Bax. H&E-stained kidney sections from cisplatin-induced AKI mice treated with recombinant FGF21 showed a relatively normal renal tissue structure, a reduced number of necrotic sites and vacuolar changes, and decreased casts, suggesting alleviated renal tubular injury. Experiments with an AKI cell model (cisplatin-treated HK-2 cells) yielded similar results as the mouse model; recombinant FGF21 significantly downregulated protein expression levels of TIM-1, C-caspase 3, and Bax. Furthermore, administration of recombinant FGF21 to cisplatin-treated AKI models significantly increased SIRT1 expression, and the beneficial effects of FGF21 on kidney injury were reversed by SIRT1 knockdown. Collectively, our results suggest that SIRT1 mediates the protective effect of FGF21 on cisplatin-induced kidney injury.

Background Long-term treatment with antiepileptic drugs such as valproic acid (VPA) and carbamazepine (CBZ) may disrupt renal tubular function. Urinary N-acetyl-beta-D-glucosaminidase (NAG) may reflect tubular function and may be useful in detecting early-stage tubular injury. To date, no study has investigated the toxic effect of VPA and CBZ on renal tubules using urinary NAG in Indonesian children. Objectives To determine the toxicity of long-term VPA and/or CBZ treatment on renal tubules in children with epilepsy by measuring urinary NAG index (iNAG). Methods This cross-sectional study was conducted from January to March 2015 at Cipto Mangunkusumo Hospital and Anakku Clinic Pondok Pinang, Jakarta. We included children aged 3 to 16 years with epilepsy on VPA (n=36), CBZ (n=14), or VPA-CBZ combination (n=14) therapy. We measured urinary levels of creatinine and NAG. The urinary NAG reference value was obtained from age-matched healthy controls (n=30). To eliminate diurnal variations in NAG, iNAG was calculated by dividing urinary NAG by urinary creatinine. A urinary iNAG of more than two standard deviations above the mean for healthy children was considered elevated. Results Mean urinary iNAG values for the control, VPA, CBZ, and combination groups were 3.01, 5.9, 4.07, and 6.9 U/g, respectively. All treated groups had higher mean urinary iNAG values compared to the control group. Urinary iNAG was increased in 11/36 children on VPA, 2/14 children on CBZ, and 9/14 children on combination therapy. Conclusion Long-term VPA use may impair renal tubular function, as shown by the increased urinary iNAG. Combination therapy increases damage in the renal tubules.

Acute kidney injury (AKI) is a common complication in cancer patients. Kidney function is closely related to patients' quality of life and tumor prognosis. Cisplatin is a highly effective anti-tumor drug. However, the use of cisplatin is limited by its nephrotoxicity. It has been reported that FGF21 has a renal-protective function, but the mechanisms by which it does so remain unclear. In this study, we show that the expression of FGF21 is significantly upregulated in both in vitro and in vivo cisplatin-induced AKI models. Administration of recombinant FGF21 to cisplatin-induced AKI mice resulted in significantly decreased blood urea nitrogen (BUN) and serum creatinine levels, as well as significantly reduced protein levels of kidney injury molecule-1 (TIM-1), C-caspase 3, and Bax. H&E-stained kidney sections from cisplatin-induced AKI mice treated with recombinant FGF21 showed a relatively normal renal tissue structure, a reduced number of necrotic sites and vacuolar changes, and decreased casts, suggesting alleviated renal tubular injury. Experiments with an AKI cell model (cisplatin-treated HK-2 cells) yielded similar results as the mouse model; recombinant FGF21 significantly downregulated protein expression levels of TIM-1, C-caspase 3, and Bax. Furthermore, administration of recombinant FGF21 to cisplatin-treated AKI models significantly increased SIRT1 expression, and the beneficial effects of FGF21 on kidney injury were reversed by SIRT1 knockdown. Collectively, our results suggest that SIRT1 mediates the protective effect of FGF21 on cisplatin-induced kidney injury. [ABSTRACT FROM AUTHOR]

Background & Aims: Patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) rs738409 polymorphism is associated with NAFLD severity and the PNPLA3 gene is expressed in the kidneys, but whether PNPLA3 rs738409 polymorphism is also associated with renal tubular injury (RTI) is uncertain. We assessed the effect of PNPLA3 genotypes on biomarkers of RTI and glomerular function in subjects with NAFLD who had either normal (nALT) or abnormal (abnALT) alanine aminotransaminase levels. Methods: Two hundred and seventeen patients with histologically proven NAFLD of which 75 had persistently nALT (below upper limit of normal for 3 months) were included. Multivariable regression analyses were undertaken to test associations between PNPLA3 genotype and biomarkers of kidney dysfunction. Results: The nALT patient group had higher urinary neutrophil gelatinase‐associated lipocalin levels (u‐NGAL, a biomarker of RTI) (P <.001), higher albuminuria (P =.039) and greater prevalence of chronic kidney disease (CKD; P =.046) than the abnALT group. The association between PNPLA3 GG genotype and risk of CKD and abnormal albuminuria remained significant after adjustment for kidney risk factors and severity of NAFLD histology, mostly in the nALT group. Similarly, PNPLA3 GG genotype was associated with higher u‐NGAL levels in the nALT group, even after adjustment for the aforementioned risk factors and glomerular filtration‐based markers (β‐coefficient: 22.29, 95% CI: 0.99‐43.60, P =.041). Conclusion: Patients with NAFLD and persistently nALT, who carry the PNPLA3 rs738409 G allele, are at higher risk of early glomerular and tubular damage. We suggest PNPLA3 genotyping may help identify patients with NAFLD at higher risk of RTI. [ABSTRACT FROM AUTHOR]

Background: Lipid metabolism imbalance is involved in the mechanism of renal tubular injury in diabetic kidney disease (DKD). Fatty acid binding protein 4 (FABP4) has been reported to participate in cellular lipid toxicity. However, the expression of FABP4 in renal tissues of DKD and its correlation with clinical/ pathological parameters and prognosis have not been studied., Methods: A retrospective cohort study was conducted in 108 hospitalized Type 2 diabetes (T2D) patients with renal injury, including 70 with DKD and 38 with NDKD (non-DKD). Clinical features, pathological findings, and follow-up parameters were collected. Serum and urine FABP4 were detected by ELISA. An immunohistochemistry stain was used to determine FABP4 in renal tubulointerstitium. A double immunofluorescence stain was employed to assess FABP4- and CD68-positive macrophages. Correlation analysis, logistic regression models, receiver operating characteristic (ROC), and Kaplan-Meier survival curve were performed for statistical analysis., Results: DKD patients had increased expression of FABP4 and ectopic fat deposition in tubules. As shown by correlation analyses, FABP4 expression in renal tubules was positively correlated with UNAG (r=0.589, p=0.044) and ESRD (r=0.740, p=0.004). Multivariate regression analysis revealed that UNAG level was correlated with FABP4 expression level above median value (odds ratio:1.154, 95% confidence interval:1.009-1.321, p=0.037). High-expression of FABP4 in renal tubules of DKD was at an increased risk of ESRD. Increased FABP4 expression in inflammatory cells was also associated with ESRD in DKD., Conclusion: High-expression of FABP4 is involved in the pathogenesis of renal tubular lipid injury and is a risk factor for poor prognosis in DKD patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ferroptosis-related renal tubular lesions play important roles in diabetic kidney disease (DKD) progression, and these pathophysiological responses are collectively described as diabetic tubulopathy (DT), which lacks an effective treatment. Total flavones from Abelmoschus manihot (TFA), a natural extract that extensively used in patients with chronic kidney disease, has been used for treatment of renal tubular injury in DKD; however, whether TFA alleviates DT and its potential mechanisms remain unclear. Hence, we investigated the effects of TFA, compared to dapagliflozin, in DT management both in vivo and in vitro, using a DKD rat model and the NRK-52 E cells. Following modeling, the DKD rats received TFA, dapagliflozin, or vehicle for 6 weeks. For the in vitro research, the NRK-52 E cells were exposed to advanced glycation end products (AGEs) plus ferrostatin-1 (Fer-1), dapagliflozin, or TFA. Changes in biochemical parameters and renal tubular injury were analyzed in vivo, while changes in ferroptosis of renal tubular cells and the ferroptosis-related proteins expression were analyzed both in vivo and in vitro. We found that TFA and dapagliflozin improved biochemical parameters, renal tubular injury, and ferroptosis in the DKD rats. Moreover, TFA and dapagliflozin inhibited ferroptosis by ameliorating iron deposition, lipid peroxidation capacity, and ferroptosis-related proteins expression in vitro, which was similar to the effects of Fer-1. Collectively, this study demonstrated that TFA treated DT in a manner similar to dapagliflozin by inhibiting ferroptosis of renal tubular cells via improving iron deposition and antioxidant capacity. Our findings provide new pharmacological evidence for TFA application in DT treatment., (© 2022 American Association for Anatomy.)

The susceptibility of the kidneys to fluoride toxicity can largely be attributed to its anatomy and function. As the filtrate moves along the complex tubular structure of each nephron, it is concentrated in the proximal and distal tubules and collecting duct. It has been frequently observed that the children suffering from renal impairments also have some symptoms of dental and skeletal fluorosis. The findings suggest that fluoride somehow interferes with renal anatomy and physiology, which may lead to renal pathogenesis. The aim of this study was to evaluate the fluoride-associated nephrotoxicity. A total of 156 patients with childhood nephrotic syndrome were screened and it was observed that 32 of them had significantly high levels (p ≤ 0.05) of fluoride in urine (4.01 ± 1.83 ppm) and serum (0.1 ± 0.013 ppm). On the basis of urinary fluoride concentration, patients were divided into two groups, namely group 1 (G-1) (n = 32) containing normal urine fluoride (0.61 ± 0.17 ppm) and group 2 (G-2) (n = 32) having high urine fluoride concentration (4.01 ± 1.83 ppm). Age-matched healthy subjects (n = 33) having normal levels of urinary fluoride (0.56 ± 0.15 ppm) were included in the study as control (group 0 (G-0)). Kidney biopsies were taken from G-1 and G-2 only, who were subjected to ultrastructural (transmission electron microscopy) and apoptotic (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling) analysis. Various subcellular ultrastructural changes including nuclear disintegration, chromosome condensation, cytoplasmic ground substance lysis, and endoplasmic reticulum blebbing were observed. Increased levels of apoptosis were observed in high fluoride group (G-2) compared to normal fluoride group (G-1). Various degrees of fluoride-associated damages to the architecture of tubular epithelia, such as cell swelling and lysis, cytoplasmic vacuolation, nuclear condensation, apoptosis, and necrosis, were observed. [ABSTRACT FROM AUTHOR]

Fine particulate matter (PM 2.5)-related health issues have received increasing attention as a worldwide public health problem, and PM 2.5 -related chronic kidney disease (CKD) has been emerging over the years. Limited research has focused on the mechanism of PM 2.5 -induced kidney disease. To investigate the impact of PM 2.5 on the kidney and its potential mechanism, we generated a PM 2.5 -exposed C57BL/6 mouse model by using Shanghai Meteorological and Environment Animal Exposure System (Shanghai-METAS) for 12 weeks, urine, blood and kidney tissues were collected. The pathological changes and the function of the kidney were measured after PM 2.5 exposure for 12 weeks. Along with glomerular damage, tubular damage was also severe in PM 2.5 -induced mice. The results of mRNA-seq indicate that pyroptosis is involved. Pyroptosis is defined as caspase-1-dependent programmed cell death in response to insults. The expression of the nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), Caspase-1, gasdermin D (GSDMD) and IL-1β was detected. NLRP3 inflammasome activation and subsequent pyroptosis were observed in PM 2.5 -exposed kidney tissues and PM 2.5 -exposed Bumpt cells too. At the meantime, the inhibitors of NLRP3 and caspase-1 were applied to the PM 2.5 exposed Bumpt cells. It turned out to have a significant rescue effect of the inhibitors. This study revealed new insights into PM 2.5 -induced kidney injury and specific kidney pathological damage, as well as morphological changes, and defined the important role of pyroptosis in PM 2.5 -induced kidney dysfunction. • This study revealed the renal pathological and functional changes in PM 2.5 -exposed mice model. • The activation of NLRP3 inflammasome-mediated pyroptosis may be contributed to PM 2.5 -induced renal injury. • Blocking NLRP3 or caspase-1 can significantly rescue PM 2.5 -induced pyroptosis. [ABSTRACT FROM AUTHOR]

Fine particulate matter (PM 2.5 )-related health issues have received increasing attention as a worldwide public health problem, and PM 2.5 -related chronic kidney disease (CKD) has been emerging over the years. Limited research has focused on the mechanism of PM 2.5 -induced kidney disease. To investigate the impact of PM 2.5 on the kidney and its potential mechanism, we generated a PM 2.5 -exposed C57BL/6 mouse model by using Shanghai Meteorological and Environment Animal Exposure System (Shanghai-METAS) for 12 weeks, urine, blood and kidney tissues were collected. The pathological changes and the function of the kidney were measured after PM 2.5 exposure for 12 weeks. Along with glomerular damage, tubular damage was also severe in PM 2.5 -induced mice. The results of mRNA-seq indicate that pyroptosis is involved. Pyroptosis is defined as caspase-1-dependent programmed cell death in response to insults. The expression of the nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), Caspase-1, gasdermin D (GSDMD) and IL-1β was detected. NLRP3 inflammasome activation and subsequent pyroptosis were observed in PM 2.5 -exposed kidney tissues and PM 2.5 -exposed Bumpt cells too. At the meantime, the inhibitors of NLRP3 and caspase-1 were applied to the PM 2.5 exposed Bumpt cells. It turned out to have a significant rescue effect of the inhibitors. This study revealed new insights into PM 2.5 -induced kidney injury and specific kidney pathological damage, as well as morphological changes, and defined the important role of pyroptosis in PM 2.5 -induced kidney dysfunction., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes and is a chronic progressive condition. It is also a common cause of end-stage renal disease (ESRD), which is characterized by proteinuria or a progressive decline in the glomerular filtration rate. Due to their dependence on high-energy and aerobic metabolism, renal tubules are more susceptible to the metabolic disturbances associated with DKD, leading to inflammation and fibrosis. Consequently, tubular injury has become a recent research focus, and significant advancements have been made in studying the role of extracellular vesicles in DKD-associated tubular injury. This review aimed to elucidate the mechanisms and potential applications of different types of extracellular vesicles in tubular injury in DKD to provide new insights for the prevention and treatment of DKD., 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 © 2023 Li, Zheng, Li, Lin, Li, Wang, Chen, Ma and Liu.)