The Impact of METTL3 on MDM2 Promotes Podocytes Injury During Diabetic Kidney Disease

Abstract

N6-Methyladenosine (m6A) methylation plays a role in various pathological processes, including renal fibrosis and aging. Our previous studies have highlighted abnormal expression of the methyltransferase enzyme, methyltransferase like 3 (METTL3), in aging kidney tissues. This study aims to elucidate the regulatory mechanisms of METTL3 in diabetic kidney disease (DKD) by establishing a conditional METTL3 knockout model. We observed elevated m6A levels in the kidneys of type I diabetic mice and in cultured mouse podocytes exposed to advanced glycation end products (AGEs). These increases were attributed to enhanced METTL3 expression. Significantly, podocyte-specific METTL3 knockdown mitigated injury in streptozotocin (STZ)-induced diabetic mice, evidenced by reduced urine albuminuria and renal pathology. We discovered that METTL3 induced abnormal m6A modification of murine double minute 2 (MDM2), which triggered its degradation in an IGF2BP2 (insulin-like growth factor 2 mRNA-binding protein 2)-dependent manner. This modification led to increased MDM2 expression, activating the Notch signalling pathway and inducing podocyte cell cycle arrest under diabetic conditions, which further released inflammatory factors and caused podocyte dedifferentiation. Our findings suggest that targeting m6A modification via METTL3 could be an effective strategy for treating DKD.