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Numerous studies have proven the critical role of macrophages in the renal fibrosis process. Notably, G Protein-coupled Estrogen Receptor 1 (GPER1), a novel estrogen receptor, has been shown to play a ubiquitous role in regulating macrophage activities and proinflammatory pathways. However, the precise role of GPER1 in macrophage-mediated renal fibrosis is unknown. In this study, we aimed to investigate the function of macrophage GPER1 in the UUO-induced renal fibrosis model. Compared to vehicle-treated ovariectomized (OVX) female and male unilateral ureteral obstruction (UUO) models, we observed that G-1 (GPER1 agonist)-treated OVX female and male UUO mice had fewer renal fibrotic lesions and less M1 and M2 macrophage infiltration in the kidney tissues. Conversely, Gper1 deletion in male UUO mice accelerated renal fibrosis and increased inflammation. In vitro studies also revealed that GPER1 activation reduced M0 macrophage polarization towards M1 or M2 phenotypes. The RNA-sequencing analysis and immunoblotting indicated that GPER1 activation was primarily involved in downregulating immune pathways activation and inactivating MAPK pathways. Tubular epithelial cells co-cultured with G-1-pretreated M1 macrophages exhibited fewer injuries and immune activation. In addition, fibroblasts co-cultured with G-1-pretreated M2 macrophages showed downregulated extracellular matrix expression. Overall, this is the first study to demonstrate the effect of GPER1 on macrophage-mediated renal fibrosis via inhibition of M1 and M2 macrophage activation. These findings indicate that GPER1 may be a promising therapeutic target for treating renal fibrosis., (© 2023. The Author(s).)

Heat-stress nephropathy (HSN) is associated with recurrent dehydration. However, the mechanisms underlying HSN remain largely unknown. In this study, we evaluated the role of dehydration in HSN and kidney injury in mice. Firstly, we found that complement was strongly activated in the mice that were exposed to dehydration; and among complement components, the interaction between C3a and its receptor, C3aR, was more closely associated with kidney injury. Then two-month-old mice were intraperitoneally injected with 2% dimethyl sulfoxide (DMSO) or the C3aR inhibitor SB290157 during dehydration. DMSO-treated mice exhibited excessive macrophage infiltration, renal cell apoptosis, and kidney fibrosis. In contrast, SB290157-treated mice had no apparent kidney injury. By fluorescence-activated cell sorting (FACS), we found that SB290157 treatment in mice remarkably inhibited macrophage infiltration and suppressed CCR2 expression in macrophages. In addition, C3a binding to C3aR promoted macrophage polarization toward the M1 phenotype and increased the production of TNF-α, which induced renal tubular epithelial cell (RTEC) apoptosis in vivo and in vitro. Interestingly, C3a treatment failed to directly induce TNF-α production and apoptosis in RTECs. However, TNF-α production in response to C3a treatment was significantly elevated when RTECs were cocultured with macrophages, suggesting that macrophages rather than RTECs are the target of C3a-C3aR interaction. At last, we proved that infusion of macrophages which highly expressed TNF-α would significantly deteriorate HSN in TNF-KO mice when they were exposed to recurrent dehydration. This study uncovers a novel mechanism underlying the pathogenesis of HSN, and a potential pathway to prevent kidney injury during dehydration., 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. Published by Elsevier GmbH.)

Diabetes may prevent kidney repair and sensitize the kidney to fibrosis or scar formation. To test this possibility, we examined renal fibrosis induced by unilateral ureteral obstruction (UUO) in diabetic mouse models. Indeed, UUO induced significantly more renal fibrosis in both Akita and STZ-induced diabetic mice than in nondiabetic mice. The diabetic mice also had more apoptosis and interstitial macrophage infiltration during UUO. In vitro, hypoxia induced higher expression of the fibrosis marker protein fibronectin in high glucose-conditioned renal tubular cells than in normal glucose cells. Mechanistically, hypoxia induced significantly more hypoxia-inducible factor-1 α (HIF-1 α) in high glucose cells than in normal glucose cells. Inhibition of HIF-1 attenuated the expression of fibronectin induced by hypoxia in high-glucose cells. Consistently, UUO induced significantly higher HIF-1α expression along with fibrosis in diabetic mice kidneys than in nondiabetic kidneys. The increased expression of fibrosis induced by UUO in diabetic mice was diminished in proximal tubule-HIF-1α-knockout mice. Together, these results indicate that diabetes sensitizes kidney tissues and cells to fibrogenesis probably by enhancing HIF-1 activation., (© 2022 Federation of American Societies for Experimental Biology.)

Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to the progression of kidney fibrosis. Although canonical Wnt signaling can trigger the activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Krüppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression are reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis. Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15 fl/fl mice and accompanied by the activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, the overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Ischemia-reperfusion injury contributes to tissue damage and organ failure in clinical settings, but the underlying mechanism remains elusive and effective therapies are still lacking. Here, we identified microRNA 687 (miR-687) as a key regulator and therapeutic target in renal ischemia-reperfusion injury. We show that miR-687 is markedly upregulated in the kidney during renal ischemia-reperfusion in mice and in cultured kidney cells during hypoxia. MiR-687 induction under these conditions was mediated by hypoxia-inducible factor-1 (HIF-1). Upon induction in vitro, miR-687 repressed the expression of phosphatase and tensin homolog (PTEN) and facilitated cell cycle progression and apoptosis. Blockade of miR-687 preserved PTEN expression and attenuated cell cycle activation and renal apoptosis, resulting in protection against kidney injury in mice. Collectively, these results unveil a novel HIF-1/miR-687/PTEN signaling pathway in ischemia-reperfusion injury that may be targeted for therapy., (Copyright © 2015 by the American Society of Nephrology.)

We present a bioinformatics database named Renal Gene Expression Database (RGED), which contains comprehensive gene expression data sets from renal disease research. The web-based interface of RGED allows users to query the gene expression profiles in various kidney-related samples, including renal cell lines, human kidney tissues and murine model kidneys. Researchers can explore certain gene profiles, the relationships between genes of interests and identify biomarkers or even drug targets in kidney diseases. The aim of this work is to provide a user-friendly utility for the renal disease research community to query expression profiles of genes of their own interest without the requirement of advanced computational skills., Availability and Implementation: Website is implemented in PHP, R, MySQL and Nginx and freely available from http://rged.wall-eva.net., Database Url: http://rged.wall-eva.net., (© The Author(s) 2014. Published by Oxford University Press.)

The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200mg/kg. Blood, liver and kidney samples were obtained at 24h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity., (Published by Elsevier Inc.)

Background/aims: Renal interstitial fibrosis is a hallmark of progressive chronic kidney disease (CKD). Previous studies reported that kruppel-like factor 15 (KLF15) is an important regulator of cardiac fibrosis and could reduce the expression of extracellular matrix in mesangial cells. However, the role of this transcription factor in renal interstitial fibrosis has not been reported., Methods: In this study, we examined KLF15 expression in the remnant kidney of 5/6 nephrectomized rats 12 or 24 weeks after operation. In vitro we examined the effect of altered KLF15 expression on the production of extracellular matrix and the pro-fibrotic factor CTGF in rat renal fibroblasts (NRK-49F), and further explored the related mechanisms., Results: The level of KLF15 was drastically decreased in the renal interstitium of 5/6 nephrectomized rats with progressive interstitial fibrosis, especially at 24 weeks. Our in vitro evidence showed that overexpression of KLF15 repressed basal and transforming growth factor-β1 (TGF-β1)-induced extracellular matrix and CTGF in NRK-49F cells. In addition, TGF-β1-mediated activation of extracellular-regulated kinase (ERK) / mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase (JNK) /MAPK downregulated KLF15 expression and increased the level of extracellular matrix and CTGF, and all these effects were completely abolished by ERK1/2 inhibitor and JNK inhibitor in NRK-49F cells., Conclusions: Our findings implicate that KLF15 plays an important role and may prove to be an antifibrotic factor in renal interstitial fibrosis through regulation of ERK/MAPK and JNK/MAPK signaling pathways., (© 2014 S. Karger AG, Basel.)

Dietary protein restriction is an important treatment for chronic kidney disease. Herein, we tested the effect of low-protein or low-protein plus ketoacids (KA) diet in a remnant kidney model. Rats with a remnant kidney were randomized to receive normal protein diet (22%), low-protein (6%) diet (LPD), or low-protein (5%) plus KA (1%) diet for 6 months. Protein restriction prevented proteinuria, decreased blood urea nitrogen levels, and renal lesions; however, the LPD retarded growth and decreased serum albumin levels. Supplementation with KA corrected these abnormalities and provided superior renal protection compared with protein restriction alone. The levels of Kruppel-like factor-15 (KLF15), a transcription factor shown to reduce cardiac fibrosis, were decreased in remnant kidneys. Protein restriction, which increased KLF15 levels in the normal kidney, partially recovered the levels of KLF15 in remnant kidney. The expression of KLF15 in mesangial cells was repressed by oxidative stress, transforming growth factor-β, and tumor necrosis factor (TNF)-α. The suppressive effect of TNF-α on KLF15 expression was mediated by TNF receptor-1 and nuclear factor-κB. Overexpression of KLF15 in mesangial and HEK293 cells significantly decreased fibronectin and type IV collagen mRNA levels. Furthermore, KLF15 knockout mice developed glomerulosclerosis following uninephrectomy. Thus, KLF15 may be an antifibrotic factor in the kidney, and its decreased expression may contribute to the progression of kidney disease.

Background/Aims: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD. Methods: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions. Results: A total of 93 mutations in PKD1 and PKD2 were identified in 98 Chinese families with ADPKD inheritance and the detection rate was 81.7% (98/120). The mutation rates of PKD1 and PKD2 were 91.4% (85/93) and 8.6% (85/93), respectively. Among the 93 mutations, 59.1% (55/93) were reported for the first time. A total of 65 mutations (26 nonsense, 33 frameshift, 2 large deletion, and 4 typical splicing mutations) were identified as definite pathogenic mutations. The remaining 28 mutations (21 missense, 3 in-frame deletion, and 4 atypical splicing mutations) were determined as probable pathogenic mutations. In addition, 9 de novo mutations were found by pedigree analysis. Correlation analysis between genotype and phenotype revealed that patients with PKD1 mutations or truncating mutations exhibited the most severe clinical outcome. Conclusion: The newly identified sites for known mutations will facilitate the early diagnosis and prediction of prognosis in patients with ADPKD, and provide fundamental genetic information for clinical intervention to prevent the inheritance of this disease in affected families. [ABSTRACT FROM AUTHOR]

Aims Cyclosporin A (CsA) is considered as an effective treatment option for steroid-resistant or-dependent patients with adult-onset minimal change disease (MCD). However, CsA resistance or dependence is also observed in these patients. Tacrolimus (TAC) is a calcineurin inhibitor that is potent in cytokine suppression. The authors aim to evaluate the efficacy and safety of TAC therapy in CsA-resistant and-dependent adult-onset MCD patients. Methods Patients with adult-onset MCD were enrolled in our department from 2008 to 2012. All patients were demonstrated to be resistant to or dependent on CsA therapy. Prednisone (0.5 mg/kg per day) combined with TAC (0.05-0.1 mg/kg per day) were prescribed to these patients for at least 6 months. The primary outcome was complete or partial remission of proteinuria. Secondary outcomes included time required for complete or partial remission, adverse events, number of relapses, and TAC dosages. Results A total of 11 MCD patients were enrolled in this observational study. The numbers of patients who presented with resistance to or dependence on CsA were 7 and 4, respectively. The total remission rate was 90.9% (10/11) with the complete remission rate 72.7% (8/11). Most remission patients achieved remission during the first 2 months of TAC therapy. Patients who presented with dependence on CsA had achieved complete remission with TAC therapy, while outcomes for CsA-resistant patients were four complete remissions, two partial remissions and one resistance. The adverse events were observed in this study included infection, diarrhoea, and worsened hypertension. Five patients who had remission experienced relapse. Conclusions Tacrolimus improves proteinuria remission in adults with CsA-resistant or -dependent MCD. [ABSTRACT FROM AUTHOR]

Background Hyperphosphataemia in patients with advanced chronic kidney disease (CKD) is associated with adverse outcomes, including vascular calcification and higher mortality rates. While phosphate lowering is an integral aspect of CKD management, the efficacy and safety of phosphate binders in a contemporary cohort of Chinese haemodialysis patients (who have different genetics and dietary patterns than other populations) has not been previously described. Moreover, sparse data are available on strategies for optimal dose titration when transitioning from a calcium-based to a polymer-based phosphate binder. Methods This randomized, double-blind, dose-titration study compared sevelamer carbonate (starting dose 800 mg three times daily) with placebo over 8 weeks' duration in Chinese CKD patients on haemodialysis. Patients were required to be using calcium-based binders prior to study start. Results In all, 205 patients were randomized (sevelamer, n = 135; placebo, n = 70); mean age was 48.6 years, 61% were male and the mean time on dialysis was 4.4 years. The mean serum phosphorus decreased significantly in patients treated with sevelamer carbonate [change −0.69 ± 0.64 mmol/L (−2.14 ± 1.98 mg/dL)] but remained persistently elevated with placebo [change −0.06 ± 0.57 mmol/L (−0.19 ± 1.76 mg/dL)] (P < 0.0001). When compared with placebo, sevelamer carbonate treatment resulted in statistically significant greater mean reductions from baseline in serum total (−17.1 versus −3.3%) and low-density lipoprotein cholesterol (−33.5 versus−7.6%) (P < 0.0001 for both). Sevelamer carbonate was well tolerated with 96% adherence compared with 97% adherence in the placebo arm. Overall, adverse events experienced by patients in the sevelamer carbonate and placebo treatment groups were similar and consistent with their underlying renal disease. Conclusions This study demonstrated that hyperphosphataemia developed quickly following the cessation of phosphate binders and remained persistently elevated in end-stage CKD in the placebo-treated group. Gradually titrating up sevelamer carbonate from an initial dose of 2.4 g/day to an average daily dose of 7.1 ± 2.5 g/day was well tolerated, safe and efficacious in contemporary Chinese haemodialysis patients. [ABSTRACT FROM PUBLISHER]

Background: The role of the mammalian target of rapamycin (mTOR) inhibition in the treatment of autosomal dominant polycystic kidney disease (ADPKD) remains unclear. This meta-analysis included all randomized controlled trials (RCTs) that used mTOR inhibitors (TORIs) to halt the progression of ADPKD. Methods: Databases including MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant trials. RCTs of TORI treatment in patients with ADPKD were included. Effects on the primary outcome [total kidney volume (TKV)] and secondary outcomes [changes in cyst volume (CV) and parenchymal volume (PV), glomerular filtration rate (GFR), proteinuria, and adverse events] were analyzed. Results: The results of 5 RCTs, which included 619 patients, were analyzed. TORIs did not significantly reduce TKV [mean difference (WMD) -90.01 ml, 95% CI -235.49 to 55.47, p = 0.23; I2 = 0%; p for heterogeneity = 0.67]. CV decreased after TORI treatment (WMD -15.08 ml, 95% CI -17.82 to -12.34, p < 0.00001), and PV did not change (WMD -0.55 ml, 95% CI -64.55 to 63.45, p = 0.99). There was no significant difference in GFR between the TORI-treated and control groups (WMD 4.94 ml/min, 95% CI -0.81 to 10.68, p = 0.09). Proteinuria was significantly higher in the TORI-treated group than in the control group (standard mean difference 0.27, 95% CI 0.09-0.44, p = 0.002). Conclusion: Long-term treatment with TORIs does not benefit patients with ADPKD. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary: Chronic inflammation, characterized by increased serum levels of tumor necrosis factor-α, interleukin-6, C-reactive protein, and plasminogen activator inhibitor-1, and the presence of inflammatory-related diseases, are seen commonly in aging. Both the dysregulation of immune cells and phenotypic changes in parenchymal cells may contribute to chronic inflammation in aging. Moreover, senescent cells are an important source of inflammatory factors. Oxidative stress, via activation of p38 and c-Jun N-terminal kinase and induction of cell senescence, is likely to play a critical role in inflammation. Endoplasmic reticulum stress also may be present in aging and be involved in inflammation. Advanced glycation end products also are important contributors to inflammation in aging. Because the kidney is a major site for the excretion, and perhaps the degradation, of advanced glycation end products and small inflammatory molecules, reduced renal function in aging may promote oxidative stress and inflammation. Chronic inflammation in turn may potentiate the initiation and progression of lesions in the aging kidney. [ABSTRACT FROM AUTHOR]

Chronic local tissue hypoxia appears to play an important role in the initiation and progression of chronic renal disease. We examined the effect of local hypoxia on cultured renal tubular epithelial and mesangial cell proliferation, dedifferentiation, and extracellular matrix synthesis. The underlying signaling mechanisms whereby hypoxia induces renal cell growth were evaluated. The roles of protein kinase C, p38 mitogen-activated protein kinase, TGF-beta1, osteopontin, and nitric oxide were determined. [ABSTRACT FROM AUTHOR]

Background The activation of complement system is associated with the development of hepatitis B virus-associated membranous nephropathy (HBV-MN) and heparin could inhibit the activation of complement system. Methods This was a three-center trial. Seventy-nine patients with HBV-MN participated in the study. The follow-up of the study consisted of two periods: Stage 1 (S1) and Stage 2 (S2). All patients received 0.5 mg entecavir plus 150–300 mg/day of irbesartan but sulodexide was prescribed during S1. They were randomized into 4 groups according to sulodexide dose: blank (Group 1), 250 lipasemic unit (lsu)/day for 1 year (Group 2), 500 lsu/day for 1 year (Group 3) and 1000 lsu/day for 6 months followed by 250 lsu/day for 6 months (Group 4). Major clinical outcomes were valid remission (VR): (1) urine albumin/creatinine ratio (UACR) < 150 mg/mmol and > 50% decline of baseline; (2) albumin > 35 g/L; (3) glomerular filtration rate (GFR) > 90 ml/(min*1.73m 2 ). Results (1) Groups 3 and 4 had significantly lower UACR and higher albumin than did Groups 1 and 2 at major visits; (2) Groups 3 and 4 achieved more VR compared with Group 1 (42.1% and 60.0% vs. 9.1%, p both < 0.05); (3) in Groups 3 and 4, instead of Groups 1 and 2, more C3 deposition in the kidney was observed in those achieving VR; (4) plasma C3a, C5a and C5b-9 decreased significantly in Groups 3 and 4 during S1. Conclusions (1) The prescription of both sulodexide and entecavir could improve the prognosis of patients with HBV-MN but their mechanisms might be different; (2) the renoprotection of sulodexide in HBV-MN might probably relate to the inhibition of complement system. [ABSTRACT FROM AUTHOR]