Diabetic kidney disease is a renal microvascular disease caused by diabetes, known as one of the most serious and lethal complications of diabetes. Early renal hypertrophy is the main pathological feature, which gradually leads to the deposition of glomerular extracellular matrix and tubulointerstitial fibrosis, eventually developing irreversible structural damage to the kidneys. Autophagy is a cell self-homeostatic mechanism that is activated under stress conditions and may serve as a protective response to the survival of renal fibrogenic cells. MicroRNA (miRNA) network may be involved in the regulation of fibrosis. The purpose of this study is to assess how miRNAs regulate diabetic kidney disease and autophagy and fibrosis in renal proximal tubular cells under high glucose conditions. Human renal proximal tubular (HK-2) cells were exposed to high glucose in vitro. Bioinformatic analysis was used to select the candidate gene for potential target regulation of miR-155, Sirt1. ATG5, ATG7 is the key to autophagosome formation, regulated by Sirt1. p53 regulates miR-155 expression as a transcription factor. MiR-155 overexpression and inhibition were achieved by transfection of miR-155 mimic and inhibit to evaluate its effect on Sirt1 and autophagy and fibrosis markers. Dual luciferase reporter assays were used to confirm the direct interaction of Sirt1 with miR-155. Overexpression and inhibition of Sirt1 gene were achieved by transfection of Sirt1 plasmid and Sirt1 si to observe its effect on P53. Chip assay experiments confirmed the direct regulation of P53 on miR-155. Under high glucose conditions, miR-155 was detected in HK-2 cells in concentration gradient, increased expression of p53 and down-regulated expression of sirt1 and autophagy-associated proteins LC3II, ATG5 and ATG7. Dual luciferase reporter assays indicate that miR-155 can target its binding to the Sirt1 3′UTR region to reduce its expression. Under high glucose conditions, over expression of miR-155 decreased the expression of LC3-II and ATG5 in HK-2 cells, while inhibition of miR-155 reversed this effect. Using chip assay testing in HK-2 cells, we demonstrated that p53 binds directly to miR-155. The signaling axis of p53, miR-155-5p, and sirt1 in autophagic process might be a critical adapting mechanism for diabetic kidney injury.

Extracellular matrix (ECM) accumulation is considered an important pathological feature of diabetic kidney disease (DKD). Histone deacetylase (HDAC) inhibitors protect against kidney injury. However, the potential mechanisms of HDACs in DKD are still largely unknown. Here, we describe a novel feedback loop composed of HDAC2 and miR-205 that regulates ECM production in tubular epithelial cells in individuals with DKD. We found that HDAC2 mRNA expression in peripheral blood was markedly higher in patients with DKD than in patients with diabetes. Nuclear HDAC2 protein expression was increased in TGFβ1-stimulated tubular epithelial cells and db/db mice. We also found that miR-205 was regulated by HDAC2 and down-regulated in TGFβ1-treated HK2 cells and db/db mice. In addition, HDAC2 reduced histone H3K9 acetylation in the miR-205 promoter region to inhibit its promoter activity and subsequently suppressed miR-205 expression through an SP1-mediated pathway. Furthermore, miR-205 directly targeted HDAC2 and inhibited HDAC2 expression. Intriguingly, miR-205 also regulated its own transcription by inhibiting HDAC2 and increasing histone H3K9 acetylation in its promoter, forming a feedback regulatory loop. Additionally, the miR-205 agonist attenuated ECM production in HK2 cells and renal interstitial fibrosis in db/db mice. In conclusion, the HDAC2/SP1/miR-205 feedback loop may be crucial for the pathogenesis of DKD.

Diabetic kidney disease (DKD) has become the primary cause of chronic renal failure in China, and renal tubulointerstitial fibrosis plays a central role in DKD progression. Urinary exosomes, which reflect kidney changes, are largely influenced by RNA-binding proteins (RBPs) in their miRNA content. Our research aimed to determine the effect of the RNA-binding protein RBMX on exosomal miRNA in DKD. We introduced a higher level of Rbmx into diabetic mice using an adenoassociated virus and isolated exosomes from their kidney tissue through advanced centrifugation techniques and specialized kits. We then conducted a series of tests, including qRT-PCR, Western blot, MitoSOX, ATP luminescence, coimmunoprecipitation, SUMOylation assays, RNA immunoprecipitation, and confocal microscopy. RBMX is found in higher levels in DKD and contributes to worsening kidney fibrosis, mitochondrial damage, and miRNA mismanagement in exosomes. It specifically binds with miR-26a, miR-23c, and miR-874 within the exosomes. This dysfunction may be linked to changes in RBMX SUMOylation. These miRNAs seem to protect against mitochondrial damage in kidney cells by targeting CERS6. DeSUMOylation of RBMX plays a crucial role in determining the makeup of miRNAs in kidney cell exosomes, impacting the protective miRNAs which regulate mitochondrial damage through their interaction with CERS6 mRNA, ultimately affecting mitochondrial health in DKD.

Diabetic kidney disease (DKD) is one of the major causes of end-stage renal disease (ESRD). To evaluate the efficacy and safety of different types of mineralocorticoid receptor antagonists (MRAs) in diabetic kidney disease patients, we conducted this network meta-analysis by performing a systematic search in PubMed, MEDLINE, EMBASE, Web of Science, the Cochrane Library, and Clinicaltrials.gov. A total of 12 randomized clinical trials with 15,492 patients applying various types of MRAs covering spironolactone, eplerenone, finerenone, esaxerenone, and apararenone were included. The efficacy outcomes were the ratio of urine albumin creatine ratio (UACR) at posttreatment vs. at baseline, change in posttreatment estimated glomerular filtration (eGFR) vs. at baseline, and change in posttreatment systolic blood pressure (SBP) vs. at baseline. The safety outcome was the number of patients suffering from hyperkalemia. High-dose finerenone (MD −0.31, 95% CI: −0.52, −0.11), esaxerenone (MD −0.54, 95% CI: −0.72, −0.30), and apararenone (MD −0.63, 95% CI: −0.90, −0.35) were associated with a superior reduction in proteinuria in patients with DKD. Regarding the change in eGFR, the results of all drugs were similar, and finerenone may have potential superiority in protecting the kidney. Compared with placebo, none of the treatments was associated with a higher probability of controlling systolic blood pressure during treatment. Moreover, spironolactone, esaxerenone, and 20 mg of finerenone presented a higher risk of hyperkalemia. This Bayesian network meta-analysis was the first to explore the optimal alternative among MRAs in the treatment of DKD and revealed the superiority of 20 mg of finerenone among MRAs in treating DKD.Systematic Review Registration: PROSPERO, identifier (CRD42022313826)

Renal tubulointerstitial fibrosis is considered as an important pathological feature of diabetic kidney disease (DKD). However, the underlying mechanism remains unclear. Polo‐like kinase2 (PLK2) is a known player in the regulation of organ fibrosis. Herein, we investigated the expression and function of PLK2 in renal tubular epithelial cells in DKD. Data from the GSE30529 datasets were subjected to analyze the differentially expressed genes (DEGs) in non‐diabetic and diabetic renal tubule samples. Molecular docking analysis and Co‐IP assay were performed to investigate the interaction between PLK2 and NOTCH1. Immunohistochemistry, immunofluorescent staining, qRT‐PCR, and western blot were performed. Our research revealed an increased expression of PLK2 in both DKD mouse kidney tissues and HK‐2 cells stimulated by high glucose (HG). Silencing PLK2 remarkably reduced the expression of the renal fibrosis‐related markers fibronectin (FN), connective tissue growth factor (CTGF) and alpha smooth muscle actin(αSMA). Furthermore, we verified the interaction between PLK2 and NOTCH1. Silencing PLK2 significantly inhibited the activation of the Notch signaling pathway, and concurrently overexpressing HES1 rescued the downregulation of FN, CTGF, and αSMA induced by transfecting si‐PLK2. Finally, we found that treatment with DAPT suppressed the activation of the Notch signaling pathway and reversed the progression of renal fibrosis caused by HG. This study demonstrates that PLK2 mediates renal tubulointerstitial fibrosis in DKD by activating the Notch signaling pathway, suggesting that PLK2 may be a potential therapeutic target for DKD.