Li Na, Zhang Jie, Yan Xuefang, Zhang Chen, Liu Hui, Shan Xiaolan, Li Jingyuan, Yang Yi, Huang Chengmin, Zhang Peng, Zhang Yun, Bu Peili
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Oncotarget. 2017 Jun 13;8(24):39592-39604. doi: 10.18632/oncotarget.17165.
Renal fibrosis participates in the progression of hypertension-induced kidney injury. The effect of SIRT3, a member of the NAD+-dependent deacetylase family, in hypertensive nephropathy remains unclear. In this study, we found that SIRT3 was reduced after angiotensin II (AngII) treatment both in vivo and in vitro. Furthermore, SIRT3-knockout mice aggravated hypertension-induced renal dysfunction and renal fibrosis via chronic AngII infusion (2000 ng/kg per minute for 42 days). On the contrary, SIRT3-overexpression mice attenuated AngII-induced kidney injury compared with wild-type mice. Remarkably, a co-localization of SIRT3 and KLF15, a kidney-enriched nuclear transcription factor, led to SIRT3 directly deacetylating KLF15, followed by decreased expression of fibronectin and collagen type IV in cultured MPC-5 podocytes. In addition, honokiol (HKL), a major bioactive compound isolated from Magnolia officinalis (Houpo), suppressed AngII-induced renal fibrosis through activating SIRT3-KLF15 signaling. Taken together, our findings implicate that a novel SIRT3-KLF15 signaling may prevent kidney injury from hypertension and HKL can act as a SIRT3-KLF15 signaling activator to protect against hypertensive nephropathy.
肾纤维化参与高血压所致肾损伤的进展。烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖性脱乙酰酶家族成员SIRT3在高血压肾病中的作用尚不清楚。在本研究中，我们发现，在体内和体外，血管紧张素II（AngII）处理后SIRT3均减少。此外，通过慢性输注AngII（每分钟2000 ng/kg，持续42天），SIRT3基因敲除小鼠加重了高血压诱导的肾功能障碍和肾纤维化。相反，与野生型小鼠相比，SIRT3过表达小鼠减轻了AngII诱导的肾损伤。值得注意的是，SIRT3与肾脏富集的核转录因子KLF15共定位，导致SIRT3直接使KLF15去乙酰化，随后培养的MPC-5足细胞中纤连蛋白和IV型胶原的表达降低。此外，厚朴酚（HKL）是从厚朴中分离出的一种主要生物活性化合物，通过激活SIRT3-KLF15信号通路抑制AngII诱导的肾纤维化。综上所述，我们的研究结果表明，一种新的SIRT3-KLF15信号通路可能预防高血压引起的肾损伤，并且HKL可作为SIRT3-KLF15信号通路激活剂来预防高血压肾病。
