The effect of METTL3 on MDM2 impairs cell cycle homeostasis in podocytes during diabetic kidney disease

Abstract

N6-Methyladenosine (m6A) methylation is involved in various pathological processes. Our previous study found abnormal expression of the methyltransferases enzyme METTL3 in aging kidney tissues, resulting in renal fibrosis and aging. In this study, we aim to elucidate its regulatory mechanisms in diabetic kidney disease (DKD) by establishing a conditional METTL3 knockout model. We observed elevated m6A levels in the kidney of mice with type I diabetes and in cultured mouse podocytes exposed to advanced glycation end-products (AGEs), which could be attributed to increased METTL3 expression. Podocyte-specific METTL3 knockdown significantly mitigated podocyte injury in streptozotocin (STZ)-induced diabetic mice, leading to reduced urine albuminuria and renal pathology. Mechanistically, METTL3 induced abnormal m6A modification of MDM2, triggering subsequent degradation in an IGF2BP2 dependent manner. Consequently, this abnormal m6A regulation induces increased MDM2 expression, activates the Notch signaling pathway, induced podocyte cell cycle re-entry under diabetic conditions, releases inflammatory factors, and induces dedifferentiation of podocytes. Thus, METTL3-mediated aberrant m6A modification plays a pivotal role in podocytes under diabetic conditions. Targeting m6A via METTL3 is a potentially effective strategy for DKD treatment.