Role of miR-34a/KLF4 axis in podocyte injury and obesity-related glomerulopathy with preliminary observations in clear cell renal cell carcinoma

Objectives: This study aimed to investigate the role of miR34a in obesity-related glomerular disease using an experimental mouse model induced by a high-fat diet and a podocyte injury model induced by palmitic acid. Materials and methods: An obese mouse model was established by high-fat feeding, followed by analysis of renal pathology, immunohistochemistry, and detection of miR34a and Krüppel-like factor 4 (KLF4) levels. In vitro experiments involved treating podocytes with varying concentrations of palmitic acid, performing Oil Red O staining, assessing related indicators and apoptosis, and transfection with miR34a mimics or inhibitors to evaluate their effects. The target relationship was validated using a luciferase assay. The differential expression of miR34a in clear cell renal cell carcinoma (ccRCC) and adjacent normal tissue was detected using RT-qPCR. Results: A high-fat diet was successfully used to establish an obese mouse model, which led to a significantly increased glomerular volume. Renal tissues exhibited decreased KLF4 and nephrin levels and increased Bak and cleaved CASP9 levels. miR34a was negatively correlated with KLF4 and positively correlated with Bak, suggesting the potential induction of apoptosis through KLF4. Cell experiments demonstrated that palmitic acid upregulated miR34a, downregulated KLF4, and induced podocyte apoptosis. Furthermore, miR34a mimics exacerbated apoptosis, whereas miR34a inhibitors alleviated apoptosis. A dual-luciferase assay confirmed that miR34a targeted and inhibited KLF4 expression. miR‐34a expression was upregulated in ccRCC compared with adjacent normal renal tissues, and this tendency was more prominent in obese patients. Conclusions: Elevated miR34a levels may contribute to podocyte injury by inhibiting KLF4, thereby promoting the progression of ORG. miR34a may also be related to the pathogenesis of ccRCC, especially in obese patients.