Wu Han, Yu Ziyang, Yang Yitian, Han Zhuoting, Pan Qingjun, Chen Ying, Yu Hongyuan, Shen Siman, Xu Li
Department of Laboratory Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
School of Medicine Xiamen University, Xiamen, China.
J Cell Mol Med. 2025 May;29(10):e70627. doi: 10.1111/jcmm.70627.
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.
N6-甲基腺苷（m6A）甲基化在包括肾纤维化和衰老在内的多种病理过程中发挥作用。我们之前的研究强调了甲基转移酶样3（METTL3）在衰老肾脏组织中的异常表达。本研究旨在通过建立条件性METTL3基因敲除模型来阐明METTL3在糖尿病肾病（DKD）中的调控机制。我们观察到I型糖尿病小鼠肾脏以及暴露于晚期糖基化终产物（AGEs）的培养小鼠足细胞中m6A水平升高。这些升高归因于METTL3表达增强。值得注意的是，足细胞特异性METTL3敲低减轻了链脲佐菌素（STZ）诱导的糖尿病小鼠的损伤，尿白蛋白尿减少和肾脏病理学表现证明了这一点。我们发现METTL3诱导鼠双微体2（MDM2）的异常m6A修饰，从而以胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）依赖的方式触发其降解。这种修饰导致MDM2表达增加，激活Notch信号通路并在糖尿病条件下诱导足细胞细胞周期停滞，进而释放炎症因子并导致足细胞去分化。我们的研究结果表明，通过METTL3靶向m6A修饰可能是治疗DKD的有效策略。
