GCKR基因及其多态性位点rs780092对肥胖相关性肾病足细胞损伤的影响及机制研究

With the epidemic of obesity, obesity-related glomerulopathy (ORG) has become a major worldwide public health problem. Genetics-involved podocyte injury contributes markedly to the development of ORG. A recent GWAS revealed that GCKR was a genetic susceptibility loci for podocyte injury in Eastern Asian populations. Furthermore, our previous studies found that GCKRrs780092C/T mutation played an important role in hepatic cell lipid contents; while lipidoses in hepatic cells increased the secretion of Fetuin-A, inducing renal dysfunction. Thus, the aim of our study is to investigate the role of GCKR (rs780092) on the progression of podocyte injury of ORG. The preliminary data showed that the expression of GCKR resulted in changes of Fetuin-A levels, and significantly associated with the risk of ORG. Based on previous findings, we planned to explore effects and mechanism of GCKR(rs780092) on podocyte injury of ORG, by using RNA inference, site-directed mutagenesis, cell transfection, and cell co-culture system in vitro (cell lines) and vivo (mice models) and clinical levels. Our study will make an important role in screening predictive SNPs for the development of ORG, laying the foundation for the prevention of ORG and providing a new trial for drug targets of ORG individualized treatment.

肥胖相关性肾病（ORG）已成为全球健康负担，遗传易感因素参与的足细胞损伤是ORG致病的重要环节。GWAS提示GCKR基因是东亚人群足细胞损伤的易感基因，本课题组前期研究发现GCKR(rs780092)导致肝脏脂质沉积，进而Fetuin-A水平增加，引起肾功能损伤。因此，GCKR基因及其多态性位点rs780092可能影响ORG足细胞损伤的进展，且通过影响Fetuin-A表达来实现的。本研究前期工作已发现GCKR影响Fetuin-A表达，且与ORG患病密切相关。本研究拟进一步在临床层面、细胞水平、动物水平运用RNA干扰、定点突变、细胞转染及细胞共培养技术，从GCKR基因表达、GCKR蛋白功能、肝细胞因子Fetuin-A水平、足细胞自噬、增殖和凋亡等方面全面探讨GCKR(rs780092)对ORG足细胞损伤的影响及机制。旨在寻找ORG有预测意义的基因位点，ORG预防和个体化治疗的药物靶点。

本项目发现肥胖能够引起肾功能损伤，脂质堆积会损伤肾小球足细胞，引起足细胞凋亡、损伤明显。本研究进一步发现，早期肾功能损伤将引起心血管早期病变患病风险增加，且增加脑卒中复发的风险。然而，脂联素能够下调可诱导体外足细胞损伤；脂联素减轻肥胖所致肾损伤，可保护肥胖相关性肾病的足细胞损伤。.本研究结果为中老年人早期心血管疾病危险因素管理提供可靠的流行病学依据，降低中老年人心脑血管疾病发病风险，改善其预后。并且进一步通过体内试验和体外试验发现脂联素能够减轻肥胖相关性肾病的肾小球足细胞损伤，为肥胖相关性肾病和早期心血管疾病预防提供可靠的个性化治疗靶点。