CircMRP4 orchestrates podocytes injury via the miR-499-5p/RRAGB/mTORC1 axis in diabetic kidney disease

Abstract

Diabetic kidney disease² (DKD) is a chronic complication of diabetes characterized by kidney damage due to persistent hyperglycemia. A growing number of evidence indicated that circular RNAs³ (circRNAs) play a crucial role in diabetes and associated complications. However, the function and mechanism of circRNAs in DKD remain unclear. Herein, we investigated the expression profiles of circRNAs in DKD mice compared to non-diabetic mice using RNA-seq analysis. A novel circRNA, circMRP4, derived from the circularization of Multidrug resistance-associated protein 4⁴ (MRP4) was identified. The expression of circMRP4 was significantly increased in both kidney tissues of DKD and mouse podocytes exposed to high glucose⁵ (HG). In addition, knockdown of circMRP4 alleviated podocytes apoptosis and inflammation induced by HG, while circMRP4 overexpression resulted in the opposite impact. Dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assay demonstrated that circMRP4 could directly target miR-499-5p which was closely associated with podocytes apoptosis and inflammation. Furthermore, circMRP4 was found to act as a sponge for miR-499-5p, leading to the upregulation of its target RRAGB, thereby activating the mTORC1/P70S6K signaling. In summary, our findings suggested that circMRP4 mediated podocytes apoptosis and inflammation in DKD by modulating the miR-499-5p/RRAGB/mTORC1/P70S6K axis, highlighting circMRP4 as a potential therapeutic target for DKD.