肾周脂肪组织源瘦素通过旁分泌作用调节肾脏Na+-K+-ATP 酶活性促进肥胖相关高血压的机制研究

The occurrence of obesity-related hypertension is related to visceral adipose tissue lesion, however, the exact mechanism still unclear. Our previous study found that for obese hypertensive rats, increased the renal sodium potassium pump activity accompanied with the abnormal expression of the leptin in perirenal adipose tissue (PRAT) and abnormal biological function of leptin. For this project, based on the previous conclusion, we plan to use the high fat diet-induced obesity hypertension rats as the object of this study, spontaneous hypertensive rats as a control group and some related gene knockout mice models serve as a complement to mechanistic study. Also combined with vivo animal transfection overexpression or silence of the PRAT local leptin, and PRAT conditioned medium of adipose tissue cell culture in vitro experiment. We aimed at: (1) Clear that the PRAT paracrine mechanism involved in leptin resistance, and the leptin signaling pathway and its target of action to promote the increase of renal Na+-K+-ATPase activity. (2) Clarify that in obesity pathological state, PRAT derived-leptin is independent of circulating leptin, acts as a direct regulator of Na+-K+-ATPase, damages the renal proximal tubule epithelial cells through paracrine mechanism, which leading to the occurrence of leptin resistance, increases the renal Na+-K+-ATP enzyme activity, reduces urinary sodium excretion, and participate in the mechanism of obesity-related hypertension.

肥胖相关高血压的发生与内脏脂肪组织病变相关，但机制仍不明确。本项目组前期研究发现，肥胖高血压大鼠出现肾脏钠钾泵活性增加的同时伴有肾周脂肪组织(PRAT)瘦素的高表达和瘦素生物学作用的异常改变。本项目在此基础上，拟以高脂饮食诱导的肥胖高血压鼠为研究对象，并以自发性高血压大鼠作为对照，一些相关的基因敲除鼠动物模型作为机制研究的补充，结合活体动物转染过表达或沉默PRAT局部瘦素，以及肾周脂肪组织条件培养基和细胞共培养等体外实验，旨在：(1)明确通过PRAT旁分泌机制导致瘦素抵抗，促进肾脏Na+-K+-ATP酶活性增加的瘦素信号通路及其主要作用靶点；(2)阐明在肥胖病理状态下，PRAT源瘦素可独立于循环瘦素，作为Na+-K+-ATP酶的直接调节因子，以旁分泌机制损伤肾近曲小管上皮细胞，导致瘦素抵抗的发生，增加肾脏Na+-K+-ATP酶活性，减少尿钠排泄，参与肥胖相关高血压的发生及发展机制。

肥胖是高血压发生发展的重要危险因素，其致高血压的机制复杂且有其特殊性。近年来，肾周脂肪组织（PRAT）功能改变在触发和加重肥胖相关血压升高中的作用越来越受到广泛关注，但具体机制尚不清楚。本研究在体内和体外实验结果证实：① 高脂饮食诱导的肥胖大鼠出现尿钠排泄减少、肾小管肥大和肾小管间质纤维化，肾脏Na/K-ATP酶活性以及肾脏Na/K-ATP酶α1亚基表达减低的同时，伴有PRAT堆积和PRAT瘦素生物学作用的异常改变。肥胖促进PRAT积聚和功能紊乱，PRAT瘦素介导氧化应激引起肾小管损伤，揭示PRAT瘦素与肥胖相关肾小管损伤之间的联系；② 肥胖大鼠肾周脂肪组织源瘦素激活Na/K-ATP 酶/Src受体复合物，进而通过ROS-SGK1-Nedd4-2和ROS-AMPK-Nedd4-2途径共同上调集合管管腔侧上皮钠离子通道（ENaC）活性及表达，增加集合管对钠的重吸收、减少尿钠排泄；③ 上调的集合管ENaC反馈激活集合管基底侧Na/K-ATP 酶/Src受体复合物，减少尿钠排泄，促进肥胖高血压的发生；④ 脂肪组织瘦素生物学作用失调对肥胖鼠肾脏的影响与Na/K-ATP 酶有关。并证实PRAT瘦素通过ROS/Na/K-ATP 酶/Scr信号转导参与肥胖相关肾小管损伤的发生发展；⑤ 肥胖致肾小管内线粒体结构与功能发生显著病理性变化，PRAT瘦素通过激活肾小管上皮细胞PKC/Nox 4/ROS信号通路及其下游线粒体/caspase 3和ROS/Na/K-ATP 酶/Scr信号转导途径导致线粒体氧化应激与损伤，共同促进肾小管上皮细胞凋亡。揭示了PRAT功能异常与肥胖肾损伤间的局部分子联系，为肥胖相关高血压的防治提供实验和理论依据。本研究的发现具有原创性，已在本领域主流杂志上投稿及部分结果已发表。

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