METTL14 aggravates podocyte injury and glomerulopathy progression through N(6)-methyladenosine-dependent downregulating of Sirt1.
METTL14 aggravates podocyte injury and glomerulopathy progression through N(6)-methyladenosine-dependent downregulating of Sirt1.
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DOI：
10.1038/s41419-021-04156-y
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发表时间：
2021-09-27
影响因子：
9
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Lu Z;Liu H;Song N;Liang Y;Zhu J;Chen J;Ning Y;Hu J;Fang Y;Teng J;Zou J;Dai Y;Ding X
足细胞在蛋白尿肾病的进展中起决定性作用。N6-甲基腺苷（m6 A）作为真核生物mRNA中含量最丰富的化学修饰，参与多种病理过程。然而，其在足细胞损伤中的作用仍不清楚。在这项研究中，我们观察到阿霉素（ADR）和糖尿病肾病小鼠肾脏中m6 A RNA水平升高和胃L14表达上调最多。在局灶节段性肾小球硬化（FSGS）和糖尿病肾病患者的肾活检样本中，以及在体外培养的人足细胞中，ADR或晚期糖基化终产物（AGE）治疗也明显增加。在功能上，我们产生了足细胞特异性胃L14缺失的小鼠，并确定了足细胞中的胃L14敲除改善了肾小球功能，减轻了ADR肾病小鼠的足细胞损伤，其特征在于自噬激活和细胞凋亡和炎症抑制。与体内实验结果相似，在ADR或AGE条件下，敲低胃L14可促进足细胞自噬，减轻足细胞凋亡和炎症反应。从机制上讲，我们发现在ADR或AGE处理的足细胞中，胃L14敲低上调了Sirt 1的水平，Sirt 1是蛋白尿肾病中一种众所周知的保护性脱乙酰酶。MeRIP-qPCR和双荧光素酶报告基因检测结果表明，胃L14可促进损伤足细胞中Sirt 1 mRNA m6 A的修饰和降解。我们的研究结果表明，胃L14依赖的RNA m6 A修饰通过转录后调节Sirt 1 mRNA参与足细胞损伤，这为足细胞病变的诊断和治疗提供了一种潜在的方法。
Podocytes are known to play a determining role in the progression of proteinuric kidney disease. N6-methyladenosine (m6A), as the most abundant chemical modification in eukaryotic mRNA, has been reported to participate in various pathological processes. However, its role in podocyte injury remains unclear. In this study, we observed the elevated m6A RNA levels and the most upregulated METTL14 expression in kidneys of mice with adriamycin (ADR) and diabetic nephropathy. METTL14 was also evidently increased in renal biopsy samples from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy and in cultured human podocytes with ADR or advanced glycation end product (AGE) treatment in vitro. Functionally, we generated mice with podocyte-specific METTL14 deletion, and identified METTL14 knockout in podocytes improved glomerular function and alleviated podocyte injury, characterized by activation of autophagy and inhibition of apoptosis and inflammation, in mice with ADR nephropathy. Similar to the results in vivo, knockdown of METTL14 facilitated autophagy and alleviated apoptosis and inflammation in podocytes under ADR or AGE condition in vitro. Mechanically, we identified METTL14 knockdown upregulated the level of Sirt1, a well-known protective deacetylase in proteinuric kidney diseases, in podocytes with ADR or AGE treatment. The results of MeRIP-qPCR and dual-luciferase reporter assay indicated METTL14 promoted Sirt1 mRNA m6A modification and degradation in injured podocytes. Our findings suggest METTL14-dependent RNA m6A modification contributes to podocyte injury through posttranscriptional regulation of Sirt1 mRNA, which provide a potential approach for the diagnosis and treatment of podocytopathies.
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