慢性肾脏病主要病理改变是肾脏纤维化，活化的成纤维细胞在该过程发挥关键调控作用。我们在前期研究中发现活化的成纤维细胞中m6A修饰水平及相关调控分子KIAA1429表达显著降低，KIAA1429基因敲除后加速小鼠肾脏纤维化进展，提示其在肾脏纤维化中发挥保护作用。进一步，结合MeRIP-seq与RNA-seq分析我们发现KIAA1429介导m6A修饰MEF2C并抑制其表达，有报道MEF2C参与组织纤维化发病。基于此，我们提出研究假设：慢性肾脏病中，成纤维细胞内KIAA1429表达下调，导致MEF2C的m6A修饰减弱与表达上调，促进成纤维细胞活化，加速肾脏纤维化进展。本项目拟综合体外细胞分子试验、基因工程小鼠在体建模以及临床标本检测研究KIAA1429介导m6A修饰在肾脏纤维化致病中的调控作用。同时借助多组学分析等探讨m6A修饰MEF2C的分子机制。本项目的开展有望为肾脏纤维化的治疗提供新的思路。

Chronic kidney disease is characterized by kidney fibrosis. The activation of fibroblasts play a critical role in the pathogenesis of kidney fibrosis. Our preliminary results showed that m6A methylation and expression of related regulatory factor KIAA1429 downregulated in activation fibroblasts derived from renal fibrotic tissue. The deletion of KIAA1429 accelerated progression of renal fibrosis. This indicates that KIAA1429-mediated m6A regulation has a protective role in kidney fibrosis. Accordingly, we hypothesized the expression of KIAA1429 reduces following kidney injury, and thereby results in reduced m6A methylation of MEF2C and increase of mRNA expression. This induces the transition of fibroblasts to activated myofibroblasts and then promotes renal fibrosis. This project aims to examine the role of KIAA1429-mediated m6A methylation in the development of renal fibrosis by in vitro molecular studies, multiple in vivo animal models of genetic engineering mouse, and clinical specimen analysis. Meanwhile, the molecular mechanism of MEF2C m6A methylation is explored through multi-omics analysis and other experiment. The conduction of this work is expected to provide help in developing novel therapeutic strategies.