m6A demethylase Fto inhibited macrophage activation and glycolysis in diabetic nephropathy via m6A/Npas2/Hif-1α axis.

Macrophage infiltration and activation is a key factor in the progression of diabetic nephropathy (DN). However, aerobic glycolysis induced by m6A methylation modification plays a key role in M1-type activation of macrophages, but the specific mechanism remains unclear in DN. In this study, the expression of m6A demethylase Fto in bone marrow derived macrophages and primary kidney macrophages from db/db mice. Loss and gain-of-function analysis of Fto were performed to assess the role of Fto in DN. Transcriptome and MeRIP-seq association analysis was performed to identified the target gene was Npas2. In this study, we found that demethylase Fto exhibits low expression in type 2 DN m6A modification of Npas2 mediated by Fto regulates macrophages M1-type activation and glucose metabolism reprogramming to participate in the process of DN. Furthermore, Fto reduces the m6A modification level of Npas2 in macrophages through a Prrc2a-dependent mechanism, and decreasing its stability. This process mediates inflammation and glycolysis in M1 macrophages by regulating the Hif-1α signaling pathway. Fto may act as a suppressor of M1 macrophages inflammation and glycolysis in DN through the m6A/Npas2/Hif-1α axis. This findings providing a new basis for the prevention and treatment of DN.