NPR3调控上皮间充质化在高血压肾脏纤维化中的作用机制研究

肾脏纤维化是高血压诱导肾损伤的重要病理学基础。我们前期全基因组关联研究发现钠尿肽受体C（NPR3）位点与东亚人群高血压密切相关，但是NPR3是否参与高血压肾纤维化尚不清楚。预实验我们发现肾小管细胞表达NPR3，敲除NPR3导致高血压肾脏损伤加重涉及上皮间充质转化（EMT）介导的纤维化，进一步通过转录组测序发现NPR3调控下游靶基因FABP1表达参与纤维化过程。因此，本项目假设敲除NPR3通过下游信号促进FABP1表达，后者通过调节脂质转运代谢促进上皮细胞向间充质转化（EMT），从而导致肾脏纤维化及损伤。本项目拟在肾小管特异性NPR3等基因敲除小鼠上构建高血压模型，研究1）敲除NPR3诱导的肾脏纤维化以及EMT的指标改变；2）NPR3调控FABP1表达参与EMT的作用机制；3)干预FABP1表达是否逆转NPR3缺失引起的肾纤维化过程，为高血压肾损伤治疗提供新的靶点以及理论依据。

Renal fibrosis is an important pathological basis of renal injury induced by hypertension. Our previous genome-wide association study found that the NPR3 locus was closely related to hypertension in East Asian population, but whether NPR3 is involved in hypertensive renal fibrosis is unclear. In a preparatory experiment, we found that NPR3 was expressed in renal tubular cells. Knockout of NPR3 led to the aggravation of renal injury in hypertension, involving the renal fibrosis mediated by epithelial-to-mesenchymal transition (EMT). Furthermore, we found that NPR3 regulated the expression of downstream target gene FABP1 by transcriptome sequencing. In this project, we hypothesize that knockout of NPR3 promotes the expression of FABP1 through downstream mechanism, which promotes EMT by regulating lipid transport metabolism and results in renal fibrosis. The present project aims to build a hypertension model in the renal tubular specific NPR3 knockout mice, to investigate 1) renal fibrosis induced by hypertension and changes of EMT indexes, after NPR3 knockout; 2) mechanisms for the regulation of FABP1 expression by NPR3 in the participation of EMT; 3) whether the intervention of FABP1 expression reverses renal fibrosis induced by NPR3 knockout. To provide a new target and theoretical basis for the treatment of hypertensive renal injury.