Podocyte injury is a critical event in the progression of chronic kidney disease (CKD), with oxidative stress as a central pathogenic mechanism. Despite the efficacy of finerenone in mitigating CKD progression, its precise cytoprotective mechanisms within podocytes remain incompletely defined. This study aimed to elucidate the role of dipeptidyl peptidase 9 (DPP9) in podocyte injury and determine whether finerenone exerts its renoprotective effects via DPP9-mediated antioxidative effects. Integrated bioinformatic analyses of single-cell and bulk transcriptomic databases (KIT, NephroSeq) were performed, with validation in renal biopsies from patients with diabetic kidney disease (DKD) and in murine models of DKD and adriamycin-induced nephropathy. In vitro, immortalized human podocyte (HPC) cells were stimulated with high glucose or adriamycin, with DPP9 knockdown or overexpression. RNA sequencing and immunoprecipitation assays were utilized to explore the underlying molecular mechanisms and protein interactions. DPP9 was significantly downregulated in injured podocytes from both human and murine models. DPP9 overexpression activated NRF2-mediated antioxidant responses, protecting podocytes from injury, whereas DPP9 depletion exacerbated cellular damage. Finerenone upregulated DPP9 protein levels, which subsequently enhanced DPP9-KEAP1 binding and competitively disrupted the NRF2-KEAP1 interaction, leading to NRF2 stabilization and activation. Consequently, finerenone improved renal function and alleviated pathological damage in vivo. In conclusion, this study identifies DPP9 as a critical mediator of podocyte antioxidant defense and establishes that the therapeutic efficacy of finerenone is, at least in part, dependent on the upregulation of DPP9.

Background The kidney critically regulates elemental homeostasis, and disruptions in elemental balance can lead to significant harm. Current research on the changes in elemental levels among chronic kidney disease (CKD) and dialysis patients presents conflicting results. This study aimed to investigate alterations in four common essential elements (selenium, calcium, copper, magnesium) in the plasma of Chinese CKD patients at different stages and dialysis patients. Methods A cross-sectional study involving 342 patients was conducted, and plasma levels of various elements were measured using atomic absorption spectrometry. Intergroup differences (ANOVA/Kruskal-Wallis/ Chi-square tests) and Bonferroni-adjusted comparisons were applied. Logistic regression (unadjusted/age-sex-adjusted) were used to evaluate the associations between essential elements and CKD progression. Pearson correlation analysis determined the correlation between elements and clinical indicators. Results As CKD progressed, plasma levels of copper and magnesium exhibited an upward trend, while selenium and calcium levels decreased. Hemodialysis improved plasma calcium and copper levels. Plasma levels of selenium, calcium, and magnesium exhibited statistically significant correlations with CKD progression. Elemental levels also correlated with various clinical indicators. Conclusions Various element levels undergo changes that may contribute to the onset and progression of CKD. Further research incorporating dietary assessment and longitudinal follow-up is needed to clarify the clinical implications of these alterations.

Introduction: Chronic kidney disease is a worldwide public health issue primarily characterized by glomerulosclerosis and the renal tubulointerstitial fibrosis. Recent studies have shown that TRPC6 is essential in renal interstitial fibrosis, although the precise mechanisms involved are not yet fully understood. Methods: UUO model was established using C57BL/6 male mice in which HK-2 cells were stimulated with TGF-β1. H&E and Masson staining were used to observe pathological changes. IHC staining was also conducted to measure the α-SMA, fibronectin (Fn), TRPC6, reactive oxygen species (ROS), and NLRP3 expressions. Scanning electron microscopy was used to observe morphological changes in the tubular cell membrane, and flow cytometry was utilized to measure ROS levels. In addition, Western blotting was performed to detect Fn, α-SMA, TRPC6, TXNIP, NLRP3, and the downstream pyroptosis-related molecule levels. Results: TRPC6 protein levels were enhanced in UUO mice and HK-2 cells upon TGF-β1 stimulation, which coincided with noticeable morphological changes associated with pyroptosis. Treatment with the TRPC6 inhibitor SAR7334 effectively reduced renal fibrosis markers and diminished levels of ROS, TXNIP, and proteins related to NLRP3-mediated pyroptosis (including NLRP3, cGSDMD, and IL-1β). Furthermore, application of the NLRP3 inhibitor MCC950 in HK-2 cells reinforced our findings, as it attenuated renal fibrosis-related proteins and counteracted the elevated levels of Fn, α-SMA, and NLRP3-mediated pyroptosis proteins observed in TGF-β1-stimulated HK-2 cells. Additionally, inhibiting TRPC6 appeared to dampen the activity of the ROS/TXNIP/NLRP3 pathway. Conclusion: TRPC6 may represent a promising target for mitigating renal interstitial fibrosis, potentially through its effects on the ROS/TXNIP regulatory pathway involving NLRP3-mediated pyroptosis.

Objective: The accurate detection of phospholipase A2 receptor (PLA2R) autoantibody is crucial in the diagnosis and monitoring of primary membranous nephropathy (pMN). While enzyme-linked immunosorbent assay (ELISA) is the commonly used detection method, its complexity and timeconsuming nature pose challenges, especially for small sample sizes. Chemiluminescence immunoassay (CLIA) has emerged as a rapid alternative for clinical immunoassays. This study aims to compare the sensitivity, specificity, and precision of CLIA and ELISA in detecting PLA2R autoantibody. Method: A total of 145 patients with biopsy-confirmed primary membranous nephropathy and 85 patients with non-membranous nephropathy were enrolled in this comparative study. CLIA and ELISA were employed to test all samples for the presence of PLA2R autoantibodies. Statistical analysis of sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) was performed using SPSS 26.0. The diagnostic value of ELISA and CLIA for pMN was analyzed using the ROC curve, and Correlation analysis was performed using Spearman. Results: Serum levels of anti-PLA2R antibody in pMN group were significantly higher than those in nMN group(P < 0.05). The accuracy of CLIA for detecting anti-PLA2R antibody was 76.96%, while ELISA showed an accuracy of 74.78%. The sensitivity for CLIA was 64.83%, compared to 60% for ELISA. However, no statistically significant difference was observed between the two methods (P > 0.05). The overall qualitative agreement of anti-PLA2R detection was 93.35% (95% confidence interval[CI] 89.47-96.3). ROC curve analysis showed that AUC of anti-PLA2R antibody detected by ELISA and CLIA were 0.8737 (95% confidence interval [CI] 0.8270-0.9204), 0.8914 (95% confidence interval [CI]0.8495-0.9332), respectively. The Spearman correlation analysis revealed a significant correlation between them(P < 0.05). Notably, CLIA demonstrated a significant time-saving advantage, particularly when the sample size was less than 200, and especially when it was less than 20. Conclusion: CLIA and ELISA showed similar accuracy and consistency in detecting anti-PLA2R antibody for primary membranous nephropathy. However, CLIA exhibited a significant advantage in terms of automation and time -saving compared to ELISA, particularly for smaller sample sizes. This finding suggests that CLIA has the potential to become a preferred and widely adopted test in the future.

The pathogenesis of glomerular diseases is strongly influenced by abnormal extracellular matrix (ECM) deposition in mesangial cells. Dipeptidyl peptidase IV (DPPIV) enzyme family contains DPP8 and DPP9 involved in multiple diseases. However, the pathogenic roles of DPP8 and DPP9 in mesangial cells ECM deposition remain unclear. In this study, we observed that DPP8 and DPP9 were significantly increased in glomerular mesangial cells and podocytes in CKD patients compared with healthy individuals, and DPP9 levels were higher in the urine of IgAN patients than in control urine. Therefore, we further explored the mechanism of DPP8 and DPP9 in mesangial cells and revealed a significant increase in the expression of DPP8 and DPP9 in human mesangial cells (HMCs) following TGF-β1 stimulation. Silencing DPP8 and DPP9 by siRNAs alleviated the expression of ECM-related proteins including collagen Ⅳ, collagen Ⅲ, fibronectin, MMP2, in TGF-β1-treated HMCs. Furthermore, DPP8 siRNA and DPP9 siRNA inhibited TGF-β1-induced phosphorylation of Smad2 and Smad3, as well as the phosphorylation of Akt in HMCs. The findings suggested the inhibition of DPP8/9 may alleviate HMCs ECM deposition induced by TGF-β1 via suppressing TGF-β1/Smad and AKT signaling pathway.

Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) is a serine/threonine phosphatase that plays a significant role in various physiological processes. However, the involvement of WIP1 in kidney remains unclear. Lipopolysaccharide (LPS) was administered to induce acute injury in mice and human kidney 2 (HK2) cells in the study. The WIP1 inhibitor, CCT007093, was administered both in vitro and in vivo to assess its effect on kidney. The single-cell sequencing (scRNA-seq) data revealed that Ppm1d mRNA reached peak on day 2 following unilateral ischemia–reperfusion injury (uni-IRI) in mice, especially in the proximal renal tubules during repair phase. Compared to the control group, WIP1 protein exhibited a significant increase in renal tubules of patients with acute tubular injury (ATI) and mice with LPS-induced acute kidney injury (AKI), as well as in LPS-injured HK2 cells. In vitro experiments showed that CCT007093 increased the protein levels of NLRP3, cleaved-Caspase1, GSDMD-N and IL-1β in HK2 cells and further reduced the viability of LPS-stimulated HK2 cells. In vivo experiments showed that inhibition of WIP1 activity with CCT007093 further increased cleaved-Caspase1, GSDMD-N protein levels in kidney tissue from mice with LPS-induced AKI. In addition, LPS induces phosphorylation of p38 MAPK, a key regulator of pyroptosis, which is further activated by CCT007093. In conclusion, inhibition of WIP1 activity acts as a positive regulator of renal tubular pyroptosis mainly through the mediation of phospho-p38 MAPK.

ABSTRACT Background: Primary membranous nephropathy (pMN) is the most common pathological type of nephrotic syndrome in adults. Therefore, it is imperative to find a better combination therapy with fewer adverse effects for patients with pMN. Methods: This study enrolled 84 patients with biopsy-proven pMN and nephrotic syndrome. Thirty patients in the low-dose multitarget regimen (LDMT) group received low-dose glucocorticoids along with tacrolimus and mycophenolate mofetil, and 54 patients in the prednisone plus intravenous cyclophosphamide regimen (PC) group received corticosteroids plus intravenous cyclophosphamide. The clinical efficacy and safety of the LDMT and PC regimens in treating pMN in adults were analyzed and compared. Results: The cumulative complete remission rate was 6.67%, 56.30%, and 83.14% at the 6 th , 12 th , and 24 th month after treatment in the LDMT group, and 16.67%, 60.84%, and 81.02% in the PC group, respectively ( P = 0.620). The generalized estimating equation analysis showed that the longer the treatment duration, the better the improvements in serum albumin and urinary protein levels, and hyperlipidemia ( P = 0.0001). However, the serum creatinine levels in both groups remained stable during the treatment period. Meanwhile, the relapse rates were comparable between the two groups (21.43% vs. 22.00%, P = 0.953). Moreover, patients in the LDMT group showed fewer adverse events than those in the PC group (46.67% vs. 72.22%, P = 0.020). Conclusions: These data indicated that the low-dose multitarget regimen, which might be an alternative treatment choice for patients with pMN, had a more favorable safety profile and non-inferior efficacy compared with prednisone plus intravenous cyclophosphamide.

目的 探讨瞬时受体电位阳离子通道(transient receptor potential canonical,TRPC)促进大鼠肾小球系膜细胞(HBZY-1)细胞外基质(extracellular matrix,ECM)沉积的作用机制.方法 免疫荧光染色方法观察 TRPC1 和TRPC6在 HBZY-1 细胞上的定位及表达;给予 AngⅡ干预 HBZY-1 细胞后,应用 qRT-PCR 和 Western blotting 方法检测 Gαq/PLCβ4/TRPC信号通路关键蛋白和 ECM 沉积指标[α-SMA、CollagenⅢ(ColⅢ)和 Fibronectin(Fn)]的mRNA和蛋白表达;siRNA技术沉默TRPC1 和TRPC6 表达后,检测 ECM沉积指标的表达;Fluo-4AM Ca2+成像技术测定细胞内Ca2+内流的变化情况.结果 TRPC1 和TRPC6 在 HBZY-1 细胞中均有表达,主要定位在细胞膜和胞质.AngⅡ刺激后,可以激活 Gαq/PLCβ4/TRPC信号通路,表现为 Gαq、PLCβ4、TRPC1 和 TRPC6 的 mRNA 和蛋白表达均升高(P<0.05).细胞内的Ca2+内流增加(P<0.01),ECM沉积指标α-SMA、ColⅢ和 Fn的 mRNA和蛋白表达上调(P<0.05).RNA干扰技术沉默TRPC1 和TRPC6 表达后,导致胞内Ca2+内流减少(P<0.05),HBZY-1 细胞ECM沉积指标的 mRNA和蛋白表达均下调(P<0.05).结果 表明,沉默TRPC表达可以抑制 AngⅡ诱导的 HBZY-1细胞 ECM沉积,且可能与减少[Ca2+]i 内流有关.结论 TRPC可能是肾脏纤维化新的治疗靶点.

End-stage renal disease（ESRD） patients undergoing outpatient hemodialysis（HD） and home peritoneal dialysis（PD） are high risk population of severe and critical types caused by SARS-CoV-2 infection. In order to improve the quality of diagnosis and treatment in dialysis patients with SARS-CoV-2 infection, we wrote this recommendation for primary care clinicians. During the epidemic period of SARS-CoV-2 infection, all patients should be instructed to strengthen self-management. Once the SARS-CoV-2 infection was found in dialysis patients, early stratified management should be carried out within 72 hours after the first positive nucleic acid or antigen test results, which includes early antiviral therapy, early recognition, and transferring severe patients from community or primary hospital to a referral hospital promptly. Guidance for dietary and sports rehabilitation after SARS-CoV-2 infection should also be started as soon as possible.

目的 探讨 TRPC6 离子通道在内质网应激(endoplasmic reticulum stress,ERS)诱导的肾小球系膜细胞(HBZY-1)凋亡中的作用及机制.方法 实验分为正常对照组(NC)、thapsigargin(TG)、TG+SKF96365 和 TG+TRPC6 siRNA组.qRT-PCR和 Western blot技术检测TRPC6 和 ERS相关蛋白(GRP78 和 Caspase12)的 mRNA和蛋白表达.流式细胞术和 Hoechst33258 方法检测细胞凋亡.Fluo-4AM Ca2+成像技术测定细胞内 Ca2+内流(intra-cellular calcium,[Ca2+]i)的变化情况.结果 TG组细胞出现核浓缩或核碎裂为特征的凋亡形态变化,细胞凋亡率增加.TRPC6 和 ERS 相关蛋白(GRP78 和 Caspase12)的表达明显高于 NC 组(P＜0.05).SKF96365 和 TRPC6 siRNA预孵育 HBZY-1 细胞可减轻细胞凋亡(P＜0.05).TG 刺激后[Ca2+]i 也增加(P＜0.05).与 TG 组相比,SKF96365 和TRPC6 siRNA处理后TRPC6、GRP78 和 Caspase12 的表达下调,并伴有[Ca2+]i 的减少(P＜0.05).结论 抑制TRPC6 可以减轻TG诱导的 HBZY-1 细胞凋亡.

Dipeptidyl peptidase 8 (DPP8) and 9 (DPP9) are widely expressed in mammals including humans, mainly locate in the cytoplasm. The DPP8 and DPP9 (DPP8/9) belong to serine proteolytic enzymes, they can recognize and cleave N-terminal dipeptides of specific substrates if proline is at the penultimate position. Because the localization of DPP8/9 is different from that of DPP4 and the substrates for DPP8/9 are not yet completely clear, their physiological and pathological roles are still being further explored. In this article, we will review the recent research advances focusing on the expression, regulation, and functions of DPP8/9 in physiology and pathology status. Emerging research results have shown that DPP8/9 is involved in various biological processes such as cell behavior, energy metabolism, and immune regulation, which plays an essential role in maintaining normal development and physiological functions of the body. DPP8/9 is also involved in pathological processes such as tumorigenesis, inflammation, and organ fibrosis. In recent years, related research on immune cell pyroptosis has made DPP8/9 a new potential target for the treatment of hematological diseases. In addition, DPP8/9 inhibitors also have great potential in the treatment of tumors and chronic kidney disease.

Gastric cancer (GC) is one of the most common malignancies worldwide. TGF‐β1 induces the epithelial–mesenchymal transition (EMT) in GC, mainly through Smad‐dependent pathways. Nevertheless, few studies have focused on the activation of non‐canonical transduction pathways. TRPC, Ca2+ entry channels, are ubiquitously expressed in various cell types and are involved in many cellular functions. However, their roles in GC are not well elucidated. This study aimed to determine whether TRPC participates in the TGF‐β1‐induced EMT of GC and to investigate the potential mechanisms. Immunofluorescence staining was performed to examine the distribution and expression of TRPCs and EMT‐related proteins in SGC‐7901 cells incubated with or without TGF‐β1. The expression of TRPC1/3/6 and EMT‐related molecules, including E‐cadherin, vimentin, and α‐SMA, was detected by qRT‐PCR and Western blotting. Additionally, the underlying mechanism was determined by treating cells with pharmacological inhibitors and examining the levels of proteins involved in the main signaling cascades using Western blotting. TRPC1/3/6 were expressed at high levels in SGC‐7901 cells. Following TGF‐β1 stimulation, the expression of vimentin, α‐SMA, and TRPC1/3/6 increased and E‐cadherin expression decreased, accompanied by activation of the Ras/Raf1/ERK1/2 signaling pathway. Notably, activation of the Ras/Raf1/ERK1/2 signaling cascade was suppressed by SKF96365 and 2‐APB. Both TRPC and ERK inhibitors mitigated EMT progression. Based on these results, TRPC1/3/6 inhibition attenuated the TGF‐β1‐induced EMT in GC by suppressing Ras/Raf1/ERK signal transduction.

Silent information regulator family protein 1 (Sirt1) has gained attention for protective effects against cardiovasc diseases. Vascular smooth muscle endothelin type B (ETB) receptors are related to the pathogenesis of cardiovascular diseases. Elevated oxidized low-density lipoprotein (ox-LDL) is associated with atherosclerosis. This study will investigate whether resveratrol (a Sirt1 activator, Res) is involved in oxidized low density lipoprotein (ox-LDL)-mediated- regulation of ETB receptors in rat superior mesenteric arteries (SMA). The rat SMA segments were cultured in the presence and absence of ox-LDL with or without Res and specific inhibitor (U0126) for the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) for 24 h. After organ culture, the contractile responses to sarafotoxin 6c (S6c) were studied using a sensitive myograph, and the ETB receptor protein expression was detected using Western blotting. The results showed that Res concentration-dependently suppressed the ox-LDL -induced up-regulation of ETB receptors expression and receptor-mediated vasoconstriction. In addition, these effects could be inhibited by U0126. Furthermore, activity of ERK1/2 phosphorylation and P65 acetylation induced by ox-LDL were blocked by Res. In conclusion, Res down-regulated ETB receptors through up-regulating Sirt1 and followed by ERK1/2/NF-кB signaling pathways in the organ culture SMA.

Background/Aims: Insulin-like growth factor-1 (IGF-1) plays important roles in cellular proliferation, differentiation, and growth. Previous studies showed that single-nucleotide polymorphisms (SNPs) of IGF-1 are associated with various diseases. This case-control study aimed to examine the relationship between IGF-1 polymorphisms and IgA nephropathy (IgAN) risk in a Chinese Han population. Methods: We recruited 351 IgAN patients and 310 healthy controls from Northwestern China. Sequenom MassARRAY was utilized to examine the genotypes of two common IGF-1 SNPs (rs1520220 and rs2195239). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by the Chi square test to evaluate the associations between IGF-1 and IgAN. Results: Our study demonstrated that IGF-1 gene rs1520220 and rs2195239 polymorphisms did not confer susceptibility to IgAN. We found no correlation between gender, blood pressure, proteinuria, eGFR, and IgAN in both SNPs. However, the rs1520220 and rs2195239 variants were correlated with M1 and E1 in patients with IgAN (M0/M1: CC vs. CG+GG: OR = 1.62, P = 0.04; E0/E1: CC vs. CG+GG: OR = 1.95, P = 0.004; GG vs. GC+CC: OR = 1.90, P = 0.004, respectively). Conclusion: These results indicate that IGF-1 gene polymorphisms play crucial roles in the histopathological progression of IgAN in the Chinese Han population.

This study planned to explore the effects of M2c macrophages on epithelial-to-mesenchymal transition (EMT) of human renal proximal tubular epithelial cells (HK-2). Human monocytic leukaemia cells were induced by TPA and IL-10 to differentiate M2c macrophages. Subsequently HK-2 cells were co-cultured with the M2c macrophages in Transwell chamber. After 48 h of co-culturing the HK-2 cells were detected in the mRNA and protein expression of E-cadherin, α-SMA and vimentin with RT-PCR, immunofluorescence and Western blot respectively. Besides, the migration ability of the HK-2 cells was estimated with Transwell migration assay. ANOVA was used to compare the difference between groups and Student's t-test to conduct multiple comparisons of two groups. P < 0.05 was considered statistically significant. The results showed that the mRNA and protein expression of α-SMA and vimentin of the HK-2 cells were increased but the E-cadherin decreased significantly after 48 h co-culturing with the M2c macrophages (P < 0.05 or P < 0.01). And the migration ability of HK-2 cells were also increased significantly (P < 0.05). It may be concluded that polarized M2c macrophages may have a promoting effect on the EMT of HK-2 cells.

Background/Aims: IFN-γ was reported to be involved in the development and progression of Immunoglobulin A nephropathy (IgAN), however, few studies have investigated the association between IFN-γ polymorphisms and IgAN. Therefore, we performed a case-control study to assess the association between IFN-γ polymorphisms and the risk of IgAN. Methods: Sequenom MassARRAY was used to genotype two SNPs (rs1861494 and rs2430561) in 351 patients with IgAN and 310 healthy controls. Associations were evaluated as odd ratios (OR) with 95% confidence intervals (CI). Results: No association was found between IFN-γ rs1861494 and IgAN risk or clinical parameters. For rs2430561, the AA genotype was more common in patients with IgAN, compared with controls (AT vs. AA: OR = 0.57, P = 0.035). IFN-γ-rs2430561 T allele may be a protective factor for IgAN susceptibility (T vs. A: OR = 0.59, P = 0.04). Subgroup analysis based on clinical features revealed no significant association between rs2430561 polymorphism and clinical data such as gender, 24-h urine protein, blood pressure, Oxford classifcation and estimated glomerular fltration rate. IgAN patients had a higher IFN-γ serum level than healthy controls and patients with rs1861494 AA genotype had a higher IFN-γ serum level compared with those with AG/GG genotypes. Conclusions: IFN-γ polymorphisms may be involved in the development and progression of IgAN.

Background/Aims: Mesangial cell proliferation and extracellular matrix accumulation (ECM) deposition play an important role in the pathogenesis of glomerulosclerosis. TRPC and PPAR-γ can regulate cell proliferation. Angiotensin II (AngII) can induce mesangial cell proliferation and affect TRPC expression. However, the mechanism has not been fully elucidated. This study was designed to investigate the role of TRPC and the effect of rosiglitazone (RSG) in the proliferation of rat glomerular mesangial cells (HBZY-1) that were stimulated by AngII and the underlying mechanisms. Methods: Immunofluorescence staining and qRT-PCR were performed to examine the expression levels of TRPCs in HBZY-1. Gene expression levels of TRPC, PPAR-γ, RGS4 (regulators of G protein signaling), the GPCR/Gαq/PLCβ4/TRPC signaling pathway and major downstream molecules (PCNA, SKP2, P21 and P27) were detected by qRT-PCR and western blotting. Additionally, changes in intracellular Ca2+ levels were determined through Fluo-4 Ca2+ imaging, and the cell cycle was analyzed by flow cytometry. Results: Our results found that TRPC1 and 6 were at higher expression levels in HBZY-1 cells. Following AngII stimulation, there were increased levels of TRPC1 and 6, Ca2+ entry, PCNA and SKP2, decreased expression levels of P21 and P27 and a reduced G0/G1 percentage. Silencing TRPC1 and 6 by siRNAs led to decrease in Ca2+ influx, G0/G1 cell cycle arrest and cell proliferation. Notably, PPAR-γ activation by RSG upregulated RGS4 expression, which can interact with the Gαq family to inhibit the Gαq-mediated signaling cascade. The results were similar to silencing TRPC1 and 6 by siRNAs. Conclusion: All these results indicate that RSG could inhibit HBZY-1 cell proliferation via the Gαq/PLCβ4/TRPC signaling pathway.

Background/Aims: Endothelial nitric oxide synthase (eNOS) is one of the most important enzymes for producting nitric oxide (NO), which regulate the function of many organs and cells. The single nucleotide polymorphisms (SNPs) of eNOS were found to be associated with many kidney diseases. However, it is lack of relevant studies to evaluate the associations between eNOS polymorphisms and immunoglobulin A nephropathy (IgAN). This case-control study aimed to evaluate the relationship between eNOS polymorphisms and IgAN. Methods: We recruited 351 IgAN patients and 310 age- and sex-matched healthy controls from Northwest China. Sequenom MassARRAY was used to detect the genotypes of two common eNOS SNPs (rs1799983 and rs2070744). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by the Chi square test to evaluate the associations between eNOS and IgAN. Phase 2.1 was used to conduct haplotype analysis. Results: In the overall analysis, we found that the rs1799983 polymorphism was associated with a decreased risk of IgAN (G/T vs. G/G: OR=0.57, 95%CI=0.34–0.96; G/T+T/T vs. G/G: OR=0.52, 95%CI=0.31–0.86; G/T vs. G/G-T/T: OR=0.60, 95%CI=0.36–0.99; Log-additive model: OR=0.48, 95%CI=0.30–0.78). Haplotype analysis indicated that Trs1799983Crs2070744 is a protective factor against IgAN (OR=0.62, 95%CI=0.42––0.92). However, no significant differences were found between the two SNPs (rs1799983 and rs2070744) and clinical features (age, sex, blood pressure, and Lee’s grade) of IgAN. Conclusion: The eNOS gene rs1799983 polymorphism and Trs1799983Crs2070744 haplotype may reduce the risk of IgAN in Chinese populations.

Background/Aims: IgA nephropathy (IgAN) is a common form of primary glomerulonephritis worldwide. Previous studies indicated that IL-10 single nucleotide polymorphisms (SNP) play an important role in IgAN pathogenesis, but the results were controversy. This study aimed to investigate the association between IL-10 SNPs (rs1800872, rs1800871, and rs1800896) with IgAN in a Chinese Han population. Methods: We conducted a case–control study that included 351 patients with IgAN and 310 age-, gender- and ethnicity-matched healthy controls. Three promoter SNPs (rs1800872, rs1800871, and rs1800896) of IL-10 were genotyped by Sequenom MassARRAY. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the relationship with IgAN. Results: We found that the rs1800896 did not correlate with IgAN risk, whereas rs1800872 and rs1800871 were significantly associated with increased IgAN risk in all genetic models. The haplotype analysis indicated that the CCA haplotype was associated with increased IgAN risk (OR = 1.36; 95% CI = 1.05–1.75). Moreover, there were no associations between these SNPs and blood pressure or gender, whereas the rs1800896 variant was correlated with higher 24-hour urine protein in patients with IgAN. Conclusion: Taken together, these results suggest that IL-10 is a susceptibility gene in patients with IgAN.

Background/Aims: FK506 is an immunosuppressive drug and a calcineurin inhibitor that has been widely used in kidney disease in recent years. FK506 shows a wide range of biological and pharmaceutical effects; however, the mechanism of its anti- proliferative effect has not been well elucidated. An IgA nephropathy (IgAN) model was used to generate a mesangial cell proliferation model. This study aims to examine the effect of FK506 on IgAN rats and the underlying mechanisms. Methods: Hematuria, proteinuria and renal function were measured. To observe the pathological conditions, we performed HE (hematoxylin - eosin) and PAS (periodic acid - schiff) staining. Transcription and protein expression levels were detected by qRT - PCR (quantitative real-time polymerase chain reaction) and Wb (western blotting). The location and semi-quantitative expression levels of TRPCs, CaN (Calcineurin) and α-SMA were examined by IHC (Immunohistochemical staining). Results: We found that FK506 could improve hematuria, proteinuria and renal function, especially in the HF (high-dose FK506) groups. Renal pathological changes were ameliorated in the treatment groups. FK506 could significantly decrease TRPCs, CaN, phosphorylation of ERK1/2 and α-SMA expression. Conclusion: Taken together, these results suggest that the therapeutic effect of FK506 on IgAN might be partially associated with the down-regulated expression of TRPC channels, CaN and phosphorylation of ERK1/2.