apelin及其受体减轻高血压肾小球硬化和间质纤维化的作用机制

高血压肾小球硬化及间质纤维化与血管紧张素Ⅱ（AngⅡ）及其1型受体（AT1）相关，AngⅡ/AT1可抑制心血管活性肽apelin及其受体（APJ）在血管内皮细胞上的表达。项目组前期研究发现在福建沿海地区apelin/APJ基因单核苷酸多态性与高血压及其血管损害相关。故提出假设：apelin/APJ可通过拮抗AngⅡ/AT1发挥高血压肾脏保护作用。本项目体内实验在AngⅡ诱导的高血压小鼠给予外源性apelin，以及腺病毒介导APJ基因转移过表达APJ，明确apelin/APJ的肾脏保护作用。体外实验以大鼠肾小球系膜细胞株及人近端肾小管上皮细胞株为研究对象，构建干扰APJ和过表达APJ的重组质粒，分别以慢病毒和腺病毒介导重组质粒转染上述细胞，验证双向调节APJ对AngⅡ/AT1及下游信号通路的影响，阐明apelin/APJ对高血压肾小球硬化和间质纤维化可能的保护机制。

Hypertensive glomerulosclerosis and interstitial fibrosis are closely related to angiotensinⅡ (AngⅡ)-angiotensin II receptor type 1 (AT1) system. The vasoactive peptide apelin and its receptor APJ can be inhibited by AngⅡ-AT1 in vascular endothelial cells. Our previous research showed that the single nucleotide polymorphisms in apelin-APJ pathway were associated with hypertension and hypertensive vascular damage in a Chinese population from the coastal area of Fujian Province. Thus we make a hypothesis that apelin/APJ has renal protective effect through antagonizing AngⅡ/AT1 in hypertension. In vivo, AngⅡ- induced hypertensive mice will be treated with exogenous apelin, or with exogenous APJ gene by adenovirus-mediated gene transfer for overexpression of APJ. In vitro, glomerular mesangial cells and human proximal tubular epithelial cells will be cultivated for lentiviruses or adenoviruses-mediated gene transfection to suppress or overexpress APJ. We aim to elucidate the possible protective mechanisms of apelin/APJ on hypertensive glomerulosclerosis and interstitial fibrosis by verifying the effect of apelin/APJ on AngⅡ/AT1 and its downstream signaling pathways. Our study may provide experimental evidences for a potential new treatment for hypertention and its target-organ damage.