ABSTRACT: The m6A modification, a prevalent epigenetic change, is implicated in various disease processes. Our previous research has revealed METTL3 abnormal expression in aging kidney tissues, correlating with its role in regulating renal fibrosis. In this study, we aim to create a conditional METTL3 knockout model to delve deeper into its regulatory mechanisms in diabetic kidney disease (DKD).Utilizing a conditional, podocyte-specific METTL3 knockout mouse model induced by STZ and transfected mouse podocytes with siMETTL3 plasmids stimulated by advanced glycation end products (AGEs) in vitro, we aim to investigate potential associations between podocyte mitotic catastrophe, the release of inflammatory factors, and diabetic kidney injury. Our focus extends to unraveling the role of METTL3/IGF2BP2 in m6A modification, particularly through MDM2 degradation.Elevated m6A levels were evident in renal tissues of type I diabetic mice and in cultured mouse podocytes exposed to AGEs, attributed to increased METTL3 expression. Podocyte-specific METTL3 knockdown significantly mitigated podocyte injury in STZ-induced diabetic mice, leading to reduced albuminuria and diminished renal pathology. Mechanistically, METTL3 induces abnormal m6A modifications sites of MDM2, triggering subsequent degradation through IGF2BP2 dependent way. Consequently, this abnormal m6A regulation instigates increased MDM2 expression, activating the Notch signaling pathway, prompting podocyte cell cycle re-entry in diabetic conditions, releasing inflammatory factors, and inducing dedifferentiation of podocytes.The aberrant m6A modification, mediated by METTL3, stands pivotal effect of podocytes during diabetic condition. Targeting m6A via METTL3, the writer enzyme, may offer a potential avenue for treating DKD.
