GPR97介导的Hippo/Yap信号通路调控在高血压肾病中的作用及分子机制

高血压是慢性肾病发生发展的最重要原因之一，高血压肾病进展到终末期肾病的主要因素之一是肾间质纤维化。G蛋白偶联受体（GPCR）作为人类疾病治疗最重要的靶点，一直受到广泛关注。GPR97是一个新发现的粘附性GPCR家族的成员，其在肾纤维化中的作用尚不清楚。我们预实验中首次证实GPR97在高血压条件下的在肾小管上皮细胞中特异表达增加并与Hippo/Yap信号通路相关，明确GPR97参与了高血压肾病的发生发展。为此，本课题以GPR97为中心，运用cre-loxp条件基因敲除技术构建特异性肾小管上皮细胞GPR97基因敲除小鼠等手段深入探讨GPR97在高血压肾病中的作用及探讨GPR97-Hippo/Yap在肾小管上皮细胞中的分子调控机制；并进一步以慢病毒敲减GPR97作为高血压肾病治疗手段的初步探索。此研究将拓展对GPR97生物学功能的新认识，为高血压肾病的防治提供新靶点和思路，具有重要的理论价值。

Hypertension is one of the most important causes in the pathogenesis of chronic kidney disease. Renal tubulointerstitial fibrosis plays a crucial role in progression of hypertensive nephropathy to end-stage renal disease. G protein-coupled receptors (GPCR) are major targets of pharmaceutical drugs. The adhesion GPCRs that are a recently defined subfamily of GPCRs take center stage in the study of human diseases. GPR97, a newly identified adhesion GPCR, is demonstrated a modulator in immune system. However, it is unknown whether GPR97 contributes to the regulation of renal functions and the role of GPR97 in hypertensive nephropathy remains unclear. Our preliminary studies showed that GPR97 was up-regulated in the kidney from mice suffered hypertensive nephropathy. We also found that GPR97 was characteristically up-regulated in renal tubular epithelial cells and involved in modulating Hippo/Yap signaling pathway. Hippo/Yap signaling pathway play an important role in the pathogenesis of renal tubulointerstitial fibrosis and was associated with regulation of inflammation and renal tubular epithelial-to-mesenchymal transition (EMT). These finding indicate that GPR97 participates in the occurrence and development of hypertensive nephropathy. Therefore, the present study is designed to explore the regulatory effect of GPR97 in hypertensive nephropathy and investigate GPR97-Hippo/Yap signaling pathway in renal tubular epithelium both in vitro and in vivo animal studies using renal tubular epithelium-specific deletion of GPR97 mice. We then evaluated the possibility of down-regulating GPR97 by lentivirus as a therapeutic drug for the treatment of hypertensive nephropathy. In this study, we postulate that GPR97 is a major modulator of Hippo/Yap signaling pathway in renal inflammation and EMT, representing a putative target to ameliorate human renal tubulointerstitial fibrosis.