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Background and Purpose: Chronic kidney disease (CKD), characterized by renal fibrosis, is a global refractory disease with few effective therapeutic strategies. It has been reported that capsaicin exerts many pharmacological effects including liver and cardiac fibrosis. However, whether capsaicin plays a therapeutic role in renal fibrosis remains unclear., Methods: We investigated antifibrotic effects of capsaicin in two mouse renal fibrosis models as follows: C57BL/6J mice were subjected to unilateral ureteral obstruction (UUO) and fed with an adenine-rich diet. We uncovered and verified the mechanisms of capsaicin in human proximal tubular epithelial cells (HK2). We mainly used histochemistry, immunohistochemistry and immunofluorescence staining, western blot assay, biochemical examination and other tools to examine the effects of capsaicin on renal fibrosis and the underlying mechanisms., Results: Capsaicin treatment significantly alleviated fibronectin and collagen depositions in the tubulointerstitium of the injured kidneys from UUO and adenine-fed mice. Meanwhile, capsaicin treatment obviously reduced α-SMA expression. Moreover, capsaicin treatment dramatically protected against the phenotypic alteration of tubular epithelial cells by increasing E-cadherin expression and decreasing vimentin expression during renal fibrosis. Mechanistically, capsaicin treatment effectively suppressed α-SMA and vimentin expressions but promoted E-cadherin expression in HK2 cells mainly through the inhibition of TGF-β1-Smad2/3 signaling., Conclusion: Capsaicin significantly ameliorated renal fibrosis possibly by retarding the activation of myofibroblasts and protecting against the phenotypic alteration of tubular epithelial cells mainly through the inhibition of TGF-β1-Smad2/3 signaling. Thus, our findings may provide a new insight into the clinical application of capsaicin in renal fibrosis., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Renal fibrosis is the main pathological characteristic of chronic kidney disease (CKD), whereas the underlying mechanisms of renal fibrosis are not clear yet. Herein, we found an increased expression of microRNA-34a (miR-34a) in renal tubular epithelial cells of patients with renal fibrosis and mice undergoing unilateral ureteral obstruction (UUO). In miR-34a -/- mice, miR-34a deficiency attenuated the progression of renal fibrosis following UUO surgery. The miR-34a overexpression promoted epithelial-to-mesenchymal transition (EMT) in cultured human renal tubular epithelial HK-2 cells, which was accompanied by sharp downregulation of Klotho, an endogenous inhibitor of renal fibrosis. Luciferase reporter assay revealed that miR-34a downregulated Klotho expression though direct binding with the 3' UTR of Klotho. Conversely, overexpression of Klotho prevented miR-34a-induced EMT in HK-2 cells. Furthermore, results showed that miR-34a was induced by transforming growth factor β1 (TGF-β1) through p53 activation, whereas dihydromyricetin could inhibit TGF-β1-induced miR-34a overexpression. Accordingly, dihydromyricetin administration dramatically restored the aberrant upregulation of miR-34a and Klotho reduction in obstructed kidney, and markedly ameliorated renal fibrosis in the Adriamycin nephropathy and UUO model mice. These findings suggested that miR-34a plays an important role in the progression of renal fibrosis, which provides new insights into the pathogenesis and treatment of CKD., (Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

This article describes the principles, attributes, and pitfalls of the many MR imaging approaches available for assessment of renal-related disorders. Tables 1 and 2 summarize the specific approach and rationale.

Background: The association between visceral adiposity index (VAI) and diabetic complications has been reported in cross-sectional studies, while the effect of VAI on complication development remains unclear. This study aims to evaluate the longitudinal association of VAI and Chinese VAI (CVAI) with the incidence of diabetic nephropathy and retinopathy using a Chinese cohort. Methods: A total of 8 948 participants with type 2 diabetes from Beijing Health Management Cohort were enrolled during 2013–2014, and followed until December 31, 2019. Nephropathy was confirmed by urine albumin/creatinine ratio and estimated glomerular filtration rate; retinopathy was diagnosed using fundus photograph. Results: The mean (SD) age was 53.35 (14.66) years, and 6 154 (68.8%) were men. During a median follow-up of 4.82 years, 467 participants developed nephropathy and 90 participants developed retinopathy. One-SD increase in VAI and CVAI levels were significantly associated with an increased risk of nephropathy, and the adjusted hazard ratios (HR) were 1.127 (95% CI 1.050–1.210) and 1.165 (95% CI 1.003–1.353), respectively. On contrary, VAI and CVAI level were not associated with retinopathy after adjusting confounding factors. Conclusion: VAI and CVAI are independently associated with the development of nephropathy, but not retinopathy in Chinese adults with diabetes. [ABSTRACT FROM AUTHOR]

Our aim was to evaluate the pathogenic role of anti-neutrophil cytoplasmic antibodies (ANCAs) in patients with IgA nephropathy (IgAN). A total of 2390 patients with biopsy-confirmed IgAN were analyzed retrospectively. Thirty-five IgAN patients with ANCA and 40 IgAN patients without ANCA were enrolled. According to the Birmingham Vasculitis Activity Score (BVAS) items, the ANCA-positive patients were further divided into two subgroups which with or without systemic symptoms. The cumulative renal survival rate was calculated using Kaplan-Meier analysis. Comparisons between groups were made using the log rank test. Among the 35 ANCA-positive patients, 14 (40%) had systemic symptoms. Compared with ANCA-positive patients without systemic symptoms, ANCA-positive patients with systemic symptoms had a shorter duration of disease (1.0 [IQR, 0.3-6.8] vs. 6.0 [IQR, 2.0-21.0], P = 0.011); showed worse renal function with lower levels of eGFR (24.2 [IQR, 11.7-74.9] vs. 100.1 [IQR, 59.6-130.2] mL/min/1.73 m2, P = 0.002), serum albumin (30.4 [IQR, 27.4-34.8] vs. 41.5 [IQR, 35.1-44.4] g/L, P = 0.001), and hemoglobin (96.1 ± 21.5 vs. 118.2 ± 22.4 g/L, P = 0.006); and presented relatively higher incidences of rapidly deteriorating kidney function (28.6 vs. 0.0%, P = 0.039) and moderate-to-severe tubular atrophy (78.6 vs. 23.8%, P = 0.001). Kaplan-Meier analysis had shown that ANCA-positive patients with systemic symptoms had lower cumulative renal survival rate compared with both ANCA-positive patients without systemic symptoms and ANCA-negative patients (log rank = 14.40, P < 0.001). Evaluation of systemic symptoms is a simple, readily available clinical tool to predictive the pathogenic role of ANCA in IgAN. [ABSTRACT FROM AUTHOR]

Renal fibrosis is the most common outcome of chronic kidney disease (CKD), while the pathogenesis of renal fibrosis is not fully understood. In this study, we first showed that the progress of renal fibrosis was positively related to serum levels of indoxyl sulfate, a typical protein-bound toxin, and that there was a close correlation between serum indoxyl sulfate levels and β-catenin expression in the kidneys ( r = 0.908, p < 0.001) of CKD patients. We then demonstrated that intraperitoneal injections of indoxyl sulfate (100 mg/kg/day) for 4 weeks in uninephrectomized mice explicitly induced renal fibrosis, which was accompanied by a significant activation of Wnt/β-catenin signaling. In vitro investigations in human renal tubular HK-2 cells revealed that indoxyl sulfate exhibited a potent ability to induce Wnt/β-catenin activation through the downregulation of sFRP5, a gene that codes for an extracellular antagonist of Wnt signaling, by increasing the DNA methylation level of its promoter CpG islands. The increased expression of DNA methyltransferases following the activation of ROS/ERK1/2 signaling was responsible for the DNA hypermethylation of sFRP5 induced by indoxyl sulfate. Conversely, treatment with 5-aza-2′-deoxycytidine, an inhibitor of DNA methyltransferases, significantly reduced indoxyl sulfate-induced sFRP5 downregulation and Wnt/β-catenin activation. In vivo, intraperitoneal injections of recombinant sFRP5 protein or 5-aza-2′-deoxycytidine substantially alleviated renal fibrosis in indoxyl sulfate-treated uninephrectomized mice. Our results suggest that indoxyl sulfate promotes renal fibrosis through the induction of DNA hypermethylation of sFRP5, and thereafter the activation of Wnt/β-catenin signaling. These findings provide new insights into the pathogenesis of renal fibrosis in CKD patients. Key messages: [ABSTRACT FROM AUTHOR]

Abstract: Sinomenine has been used to treat autoimmune diseases for centuries. However, the mechanism underlying its therapeutic effects remains unknown. Increasing recognition of the importance of the Th1/Th2 imbalance in nephritis has raised the questions of whether there is a Th1/Th2 imbalance in patients with mesangial proliferative nephritis (MsPGN) and whether sinomenine can modulate the Th1/Th2 imbalance. In this study, 25 MsPGN patients were treated with sinomenine and followed for 3 months. The expression of T-bet and GATA-3 mRNA in peripheral blood mononuclear cells (PBMCs) and the serum levels of interferon-γ (IFN-γ), interleukin (IL)-4, and IL-10 were studied at month 0, month 1, and month 3. The intra-renal expression of T-bet and GATA-3 was studied via immunohistochemistry. Results reveal that PBMCs from MsPGN patients expressed high levels of T-bet mRNA and low levels of GATA-3 mRNA, and the T-bet/GATA-3 ratio in MsPGN patients was significantly higher than that in healthy donors. Meanwhile, MsPGN patients were found to have simultaneously elevated IFN-γ values and decreased IL-10 values. Immunohistochemistry revealed increased T-bet and decreased GATA-3 expression in renal tissues from MsPGN patients. Moreover, sinomenine was found to cause a decrease in T-bet mRNA expression, resulting in a drop in the T-bet/GATA-3 ratio. Sinomenine was also found to elicit a decrease in the serum levels of IFN-γ. These results suggest that a shift toward the Th1 pathway of Th cell activation occurs in MsPGN patients, and that sinomenine has the potential to counter this shift in the Th1/Th2 balance and thereby produce therapeutic effects. [Copyright &y& Elsevier]

Renal oncocytosis is a very rare entity. Although it has been described in pathology and surgery literature, the imaging findings of renal oncocytosis have not yet been described in the radiology literature. We present three cases of renal oncocytosis. The imaging features and clinical considerations are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Triptolide has been used extensively in China for the treatment of autoimmune diseases and tumor for many centuries. Nevertheless, little is known about its exact immunosuppressive and anti-inflammatory properties. Increasing recognition of the importance of renal tubular epithelial cells (TECs) in renal diseases raises the question whether triptolide can regulate TEC activity. In this study, various cultured human and murine TECs were exposed to tumor necrotic factor-α (TNF-α) and triptolide, followed to examine the expression of B7-H1 and B7-DC. Flow cytometric analysis revealed that B7-H1 but not B7-DC constitutively expresses on TECs, and the B7-H1 protein expression was profoundly up-regulated by the stimulation of TNF-α with a dose-dependent manner. However, triptolide under non-cytotoxic concentration could down-regulate B7-H1 expression on activated TECs at both mRNA and protein level. This effect was transcription factor NF-κB dependent. Interestingly, the significant damping effect of triptolide on B7-H1 signal could promote interleukin-2 production by T cell hybridoma (C10) after antigen presentation and enhance cytokine (IFN-γ and IL-2) secretion by anti-CD3 activated T cells. Our results indicated that triptolide could regulate TEC activity via B7-H1, in addition to previously reported it directly affects the production of some inflammatory factors by T cells, tumor cells and peripheral blood mononuclear cells. [Copyright &y& Elsevier]

Highlights • AAІ inhibits Slit2-induced migration and tube formation of HUVECs; • Impaired angiogenesis by AA is involved in inactivated Slit2/Robo-NCK signaling. • Overexpression of NCK1 can rescue AAІ-impaired angiogenesis. Abstract Robo1/Robo2-NCK1/NCK2 signaling pathway controls endothelial cell sprouting and migration induced by Slit2 or VEGF, but whether it is involved in peritubular capillary (PTC) rarefaction of Aristolochic acid nephropathy (AAN) is unclear. In the present study, we evaluated whether AA exerts antiangiogenic effects by targeting this signaling pathways in HUVECs. HUVECs or lentivirus-mediated NCK1-overexpressing HUVECs were stimulated with AA (1, 2 or 3 μg/ml) in the absence or presence of 6 nM Slit2. Our results showed that AAІ (1–3 μg/ml) dose-dependently inhibited the migration and tube formation of HUVECs. This inhibition was in parallel with down-regulated mRNA and protein expression of Slit2/Robo1/Robo2-NCK1/NCK2 signaling pathway. Importantly, overexpression of NCK1 rescued AAІ-impaired angiogenesis, as evidenced by the increase of cell migration and tube formation of HUVECs in response to Slit2. The down-regulation of NCK2 and decreased activation of Rac1 was also restored by overexpression of NCK1. Taken together, our findings show that AA inhibits Slit2-induced migration and tube formation via inactivation of Robo1/Robo2-NCK1/NCK2 signaling pathway in HUVECs, and NCK1 might be a potential agent for vascular remodeling in AAN and diseases associated with impaired angiogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by progressive tubulointerstitial fibrosis, chronic renal failure and urothelial cancer. Our previous study showed that bone morphogenetic protein-7 (BMP-7) could attenuate AA-induced epithelial-to-mesenchymal transition (EMT) in human proximal tubule epithelial cells (PTEC). However, how gremlin (a BMP-7 antagonist) antagonizes the BMP-7 action in PTEC remained unsolved. The aim of the current study was to investigate the role of gremlin in AA-induced EMT in PTEC (HK-2 cells). HK-2 cells were treated with AA (10μmol/L) for periods up to 72h. Cell viability was determined by tetrazolium dye (MTT) assay. Morphological changes were assessed by phase-contrast microscopy. Markers of EMT, including E-cadherin and α-smooth muscle actin (α-SMA) were detected by indirect immunofluorescence stains. The BMP-7 and gremlin mRNA and protein expression in HK-2 cells were analyzed by quantitative real-time PCR (real-time RT-PCR) and western blotting after exposure to AA. The level of phosphorylated Smad1/5/8, a marker of BMP-7 activity, was also determined by western blot analysis. Cells were transfected with gremlin siRNA to determine the effects of gremlin knockdown on markers of EMT following treatment with AA. Our results indicated that AA-induced EMT was associated with acquisition of fibroblast-like cell shape, loss of E-cadherin, and increases of alpha-SMA and collagen type I. Interestingly, exposure of HK-2 cells to 10μmol/L AA increased the mRNA and protein expression of gremlin in HK-2 cells. This increase was in parallel with a decrease in BMP-7 expression and a down-regulation of phosphorylated Smad1/5/8 protein levels. Moreover, transfection with siRNA to gremlin was able to recover BMP-7 signaling activity, and attenuate EMT-associated phenotypic changes induced by AA. Together, these observations strongly suggest that gremlin plays a critical role in the modulation of reno-protective action of BMP, and that inhibition of gremlin will be a promising means of developmenting novel treatments for AAN. [Copyright &y& Elsevier]

Abstract: Aristolochic acid nephropathy (AAN) is regarded as a kind of rapidly progressive renal fibrosis caused by the ingestion of herbal remedies containing aristolochic acid (AA). Recent studies showed that bone morphogenetic protein-7 (BMP-7) exerts beneficial effects on acute and chronic kidney injuries induced by different pathological conditions. We examined whether BMP-7 protects human renal tubular epithelial cells (HK-2) against AA-induced injury in vitro. HK-2 cells were cultured with different concentrations of AA and BMP-7 for 48h. Cell viability was determined by Cell Counting Kit-8 assay and lactate dehydrogenase (LDH) release. The apoptosis rate and the activity of caspase 3 protease were also examined. Epithelial-to-mesenchymal transition (EMT) was determined by cell morphology, E-cadherin and α-smooth muscle actin (α-SMA) protein expression, and TGF-β1 and collagen III secretion. Additionally, the effect of anti-TGF-β1 antibody on AA-induced EMT was assessed. Our results indicated that BMP-7 significantly increased cell proliferation, decreased apoptosis rate and attenuated activation of caspase-3, resulting in the protection of HK-2 cells from AA-induced cytotoxicity. In addition, studies on EMT revealed that BMP-7 could inhibit AA-induced myofibroblast phenotype and restored the epithelial morphology in a dose-dependent manner. It was partially through reducing the activation of a myofibroblast phenotype and production TGF-β1. Treatment with neutralizing anti-TGF-β1 antibody also blocked AA-induced EMT and collagen III secretion. Together, these observations strongly suggest that BMP-7 is a potent inhibitor of AA-induced renal tubular epithelial cell injury and might be a promising agent for aristolochic acid-induced kidney damage. [Copyright &y& Elsevier]