CircRNA-0013747 Promotes Mesangial Cell Proliferation in Immunoglobulin A Nephropathy through Modulation of the Warburg Effect.

Abstract

Abstract: Immunoglobulin A nephropathy (IgAN) is characterized by aberrant mesangial cell (MC) proliferation, which is a critical determinant of glomerular sclerosis and renal dysfunction. Previous studies have highlighted the role of pyruvate kinase M2 (PKM2)- mediated aerobic glycolysis in promoting MC growth and the progression of kidney diseases. However, the precise mechanisms underlying PKM2 dysregulation in IgAN remain unclear. Circular RNAs (circRNAs), a class of noncoding RNAs, have emerged as pivotal regulators in various diseases, yet their role in IgAN has not been fully elucidated. In this study, we investigated the expression and functional significance of circRNA_0013747 in IgAN, focusing on its interaction with microRNA-330-3p (miR-330-3p) and its downstream effects on PKM2-mediated aerobic glycolysis. Our results demonstrated a significant upregulation of circRNA_0013747 in kidney biopsy samples from IgAN patients. Functional analyses revealed that circRNA_0013747 promoted MC proliferation and activated PKM2-mediated aerobic glycolysis. Importantly, these effects were attenuated by the upregulation of miR-330-3p, which was found to physically interact with circRNA_0013747, thereby inhibiting its function. Mechanistically, circRNA_0013747 acted as a sponge for miR-330-3p, relieving its suppressive effects on PKM2 expression. These findings suggest that circRNA_0013747 enhances glycolysis and proliferation in MCs through modulation of the miR-330-3p/PKM2 signaling axis. These results offer novel insights into the pathogenesis of IgAN and could contribute to new therapeutic approaches for this disease. Specifically, targeting circRNA_0013747 or modulating its interaction with miR-330-3p may provide a means to inhibit MC proliferation and aerobic glycolysis, thereby slowing the progression of IgAN and preserving renal function. Such therapeutic strategies hold the promise of substantial benefits for patients with IgAN and could pave the path toward developing more potent treatments for a wider range of renal diseases.