Fasudil attenuates oxidative stress-induced partial epithelial-mesenchymal transition of tubular epithelial cells in hyperuricemic nephropathy via activating Nrf2.

Anti-partial epithelial-mesenchymal transition (pEMT) treatment of renal tubular epithelial cells (TECs) represents a promising therapeutic approach. Hyperuricemia nephropathy (HN) arises as a consequence of hyperuricemia (HUA)-induced tubulointerstitial fibrosis (TIF). Studies have suggested that the Ras homolog member A (RhoA)/Rho-associated kinase (ROCK) pathway is a crucial signaling transduction system in renal fibrosis. Fasudil, a RhoA/ROCK inhibitor, has exhibited the potential to prevent fibrosis progress. However, its impact on the pEMT of TECs in HN remains unclear. Here, an HN rat model and an uric acid (UA)-stimulated human kidney 2 (HK2) cell model were established and treated with Fasudil to explore its effects. Furthermore, the underlying mechanism of action involved in the attenuation of pEMT in TECs by Fasudil during HN was probed by using multiple molecular approaches. The HN rat model exhibited significant renal dysfunction and histopathological damage, whereas in vitro and in vivo experiments further confirmed the pEMT status accompanied by RhoA/ROCK pathway activation and oxidative stress in tubular cells exposed to UA. Notably, Fasudil ameliorated these pathological changes, and this was consistent with the trend of ROCK silencing in vitro. Mechanistically, we identified the Neh2 domain of nuclear factor erythroid 2-related factor 2 (Nrf2) as a target of Fasudil for the first time. Fasudil targets Nrf2 activation and antagonizes oxidative stress to attenuate the pEMT of TECs in HN. Our findings suggest that Fasudil attenuates oxidative stress-induced pEMT of TECs in HN by targeting Nrf2 activation. Thus, Fasudil is a potential therapeutic agent for the treatment of HN.

lncRNA TUG1 regulates hyperuricemia-induced renal fibrosis in a rat model.

Renal fibrosis is most common among chronic kidney diseases. Molecular studies have shown that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) participate in renal fibrosis, while the roles of lncRNA taurine upregulated gene 1 (TUG1) and miR-140-3p in hyperuricemia-induced renal fibrosis remain less investigated. In this study, a rat hyperuricemia model is constructed by oral administration of adenine. TUG1, miR-140-3p, and cathepsin D (CtsD) expression levels in rat models are measured. After altering TUG1, miR-140-3p, or CtsD expression in modelled rats, biochemical indices, including uric acid (UA), serum creatine (SCr), blood urea nitrogen (BUN), and 24-h urine protein are detected, pathological changes in the renal tissues, and renal fibrosis are examined. In renal tissues from hyperuricemic rats, TUG1 and CtsD are upregulated, while miR-140-3p is downregulated. Inhibiting TUG1 or CtsD or upregulating miR-140-3p relieves renal fibrosis in hyperuricemic rats. Downregulated miR-140-3p reverses the therapeutic effect of TUG1 reduction, while overexpression of CtsD abolishes the role of miR-140-3p upregulation in renal fibrosis. Collectively, this study highlights that TUG1 inhibition upregulates miR-140-3p to ameliorate renal fibrosis in hyperuricemic rats by inhibiting CtsD.

Depleted HDAC3 attenuates hyperuricemia-induced renal interstitial fibrosis via miR-19b-3p/SF3B3 axis.

Dysfunctional histone deacetylases (HDACs) elicit unrestrained fibrosis and damage to organs. With regard to the link between HDACs and fibrosis, this research is practiced to decipher the concrete mechanism of HDAC3 in hyperuricemia (HN)-induced renal interstitial fibrosis (RIF) from microRNA-19b-3p/splicing factor 3b subunit 3 (miR-19b-3p/SF3B3) axis.The HN model was established on rats to induce RIF by oral administration of adenine and potassium oxalate. HN rats were injected with miR-19b-3p- or HDAC3-related vectors to figure out their effects on RIF through detecting 24-h urine protein, uric acid (UA), blood urea nitrogen (BUN) and serum creatinine (Scr) contents and α-smooth muscle actin (α-SMA), transforming growth factor ß1 (TGF-ß1) and fibronectin (FN) contents in renal tissues and observing pathological damages and RIF index of renal tissues. HDAC3, miR-19b-3p and SF3B3 expression in renal tissues were tested, along with their interactions.Elevated HDAC3 and SF3B3 and reduced miR-19b-3p were displayed in renal tissues of HN rats. Suppressed HDAC3 or promoted miR-19b-3p relieved HN-induced RIF, as reflected by their inhibitory effects on 24 h urine protein, UA, BUN, Scr, α-SMA, TGF-ß1, and FN contents and RIF index and their ameliorated effects on pathological damages of renal tissues. HDAC3 bound to the promoter of miR-19b-3p to regulate SF3B3. MiR-19b-3p depletion abrogated down-regulated HDAC3-induced effects on HN-induced RIF.It is delineated that depressed HDAC3 relives HN-induced RIF through restoring miR-19b-3p and knocking down SF3B3, replenishing the references for RIF curing.

MIR17HG genetic variations affect the susceptibility of IgA nephropathy in Chinese Han people.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide. It accounts for approximately 30 ~ 40% of glomerular diseases in China. However, the exact pathogenesis of IgAN is not well established. This study aimed to explore the association between MIR17HG polymorphisms and IgAN susceptibility. METHODS: Six single nucleotide polymorphisms (SNPs) of MIR17HG were genotyped in 417 patients with IgAN and 424 healthy controls. The association analysis was conducted by logistic regression adjusted for age and gender in multiple genetic models and different subgroups. RESULTS: Our results revealed that rs72640334 and rs1428 increased the susceptibility to IgAN in total populations (p < 0.05). The stratification analysis by age indicated that rs72640334 enhanced the risk of IgAN people older than 35 years, while rs7318578 played a protective role in the development of IgAN patients aged >35 years (p < 0.05). In addition, MIR17HG-rs72640334 could facilitate the occurrence of IgAN in females (p < 0.05). In Lee's grade III-Vsubgroup, rs72640334 and rs7336610 have an increasing effect on IgAN risk, while rs7318578 has a decreasing effect on IgAN susceptibility (p < 0.05). CONCLUSIONS: Our findings suggested that MIR17HG genetic polymorphisms were correlated with IgAN susceptibility. It provided new evidence for the potential molecular mechanism of IgAN and may serve as a new biomarker for the treatment and early diagnosis of IgAN.

The Rho kinase signaling pathway participates in tubular mitochondrial oxidative injury and apoptosis in uric acid nephropathy.

INTRODUCTION: Oxidative stress is a pathologic feature of hyperuricemia that is highly prevalent and that contributes to kidney tubular interstitial fibrosis. Rho-kinase is closely related to mitochondrial-induced oxidative stress. Herein, we designed a study to explore the expression and role of Rho-kinase in hyperuricemia nephropathy. The secondary objective was to investigate whether the Rho-kinase signaling pathway regulates hyperuricemic tubular oxidative injury and apoptosis via the mitochondrial pathway in addition to the mechanisms that are involved. MATERIALS AND METHODS: HK-2 cells were divided into the following five groups: normal; uric acid (UA); UA+Fasudil; UA+ROCK1 si-RNA; and UA+sc-siRNA. Rho-kinase activity, mitochondrial oxidative injury, and apoptosis-related protein levels were measured in each group. A t-test was used to analyze the difference between groups. RESULTS: Myosin phosphatase target subunit 1 (MYPT1) overexpression was shown in HK-2 cells, which was caused by UA. High concentrations of UA also up-regulated Rho-kinase expression and mitochondrial and apoptosis-related protein expression, while treatment with fasudil and ROCK1 si-RNA significantly attenuated these responses. CONCLUSION: The Rho-kinase signaling pathway participates in tubular mitochondrial oxidative injury and apoptosis via regulating mitochondrial dyneins/biogenic genes in UA nephropathy, which suggests that the mitochondrial pathway might be a potential therapeutic target for hyperuricemia nephropathy.

Potential signaling pathway through which Notch regulates oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose.

Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes mellitus, and glomerular sclerosis and renal tubular interstitial fibrosis are the main pathological features. Current evidence indicates that the Notch pathway can mediate the impairment of renal tubular function and induce angiogenesis and renal interstitial fibrosis. This study was conducted to explore the potential signaling pathway through which Notch regulates oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose. mRNA and protein expression levels were assessed using real-time PCR and Western blot, respectively. The protein expression levels of Jaggedl, Notchl, pro-caspase-3, Drpl, and PGC-1α were increased by high glucose, but N-[N-(3,5-difluorohenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT; an inhibitor of the Notch signaling pathway) reversed these effects. Furthermore, DAPT reduced the mRNA expression of Jaggedl, Notchl, MnSOD2, Drpl, and PGC-1α in renal tubular epithelial cells induced by high glucose. In conclusion, the Notch signaling pathway may regulate oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose by regulating mitochondrial dynein and biogenesis genes, which can accelerate renal interstitial fibrosis in DN. The Notch signaling pathway might be a potential therapeutic target for DN, and DAPT might become a potential drug for the treatment of DN.

Sequential Engineering of Ternary CuFeNi with a Vertically Layered Structure for Efficient and Bifunctional Catalysis of the Oxygen and Hydrogen Evolution Reactions.

Developing efficient and earth-abundant electrocatalysts for electrochemical water splitting is greatly desired due to growing energy demands. Herein, we develop a promising hierarchical nickel-iron-copper nitride electrode that is fabricated via a three-step process, starting with a hydrothermal synthesis of nickel-iron hydroxide on nickel foam and followed by the direct growth of copper metal-organic frameworks and, finally, low temperature ammonization. This approach yields a material that is an efficient catalyst for both the oxygen evolution reaction and the hydrogen evolution reaction. The as-fabricated heterostructured nickel-iron-copper nitride electrode exhibits an excellent activity with an overpotential of only 121 mV for the oxygen evolution reaction and an even a lower overpotential of 33 mV for the hydrogen evolution reaction. Additionally, this structure displays strong long-term stability with only a negligible increase in potential after 500 cycles of uninterrupted cyclic voltammetry testing. To the best of our knowledge, this as-prepared hierarchical nickel-iron-copper nitride is one of the most promising alternatives for the electrochemical oxygen and hydrogen evolution reactions.