从SIRT1依赖的信号通路探讨蝉花延缓高血压肾损害的作用机制

Hypertensive renal injury(HRI) is among the first three causes of the end-stage renal disease. Glomerulosclerosis and renal interstitial fibrosis (RIF) not only play a key role in processes of HRI, but also are a phenotype of organ senescence in essential. Under pathological condition, senescence-associated gene SIRT1 relates to renal tubular epithelial cell transdifferentiation,apoptosis, glomerulosclerosis and RIF. Compared with cordyceps sinensis, cordyceps cicadae has similar active constituent, but difference flavor and nature. Its sweet flavor and cold-natured characteristic make it fitter to be used under the condition of Yin Deficiency Fire Hyperactivity and arthralgia spasm of kidney collaterals, which is the main cause and pathogenesis of HRI according to the traditional Chinese medicine (TCM) theory. Research result suggested cordyceps cicadae not only has anti-aging effect,but also can ameliorate glomerulosclerosis and RIF. According to the theory of Different Diseases in Same Treatment of TCM, we Put forward the hypothesis that cordyceps cicadae could ameliorate HRI by inhibiting epithelial-myofibroblast transdifferentiation and apoptosis in renal tubular epithelial cell via SIRT1 and its downstream signal pathway. We will investigate the mechanism of action and specific target point, through which cordyceps cicadae ameliorates HRI, from system,organ ,cellular and molecular level in vivo and vitro.

高血压肾损害是终末期肾病的前三位病因。肾小球硬化和间质纤维化在其中扮演重要角色，上述病理变化实质上是脏器衰老的一种表现。病理状态下衰老相关基因SIRT1与肾脏固有细胞的转分化、凋亡，进而导致肾小球硬化和间质纤维化有密切关系。中药蝉花的有效成份与冬虫夏草相似，属优质虫草，且其味甘咸性寒异于甘温之虫草，具有滋阴清热、散结通络之功效，更符合高血压肾损害阴虚火旺，肾络瘀痹，络息成积之病机。研究表明蝉花既有抗衰老作用，又能延缓肾小球硬化和肾间质纤维化。根据中医"异病同治"理论，本课题提出了"调控SIRT1及其下游通路，抑制高血压病理状态下肾脏固有细胞转分化及凋亡是蝉花延缓高血压肾损害的作用机制之一"的假说。拟以原发性高血压肾损害大鼠、肾小球内皮细胞、足细胞、系膜细胞和小管上皮细胞为研究对象，从体内、体外两方面，在整体、器官、细胞学和分子生物学等不同层面上，探讨蝉花防治高血压肾损害作用机制。

高血压肾损害是终末期肾病的第三位病因。肾小球硬化和间质纤维化在其中扮演重要角色，上述病理变化实质上是脏器衰老的一种表现。高血压状态下衰老相关基因SIRT1表达下调，其与肾脏固有细胞转分化及凋亡密切相关，进而导致肾小球硬化和间质纤维化。我们将高血压肾损害中医病机概括为“阴虚火旺，肾络瘀痹，络息成积”，制定了“滋阴清热，通络散结”的治疗原则。中药蝉花属优质虫草，其味甘咸性寒异于甘温之虫草，具有滋阴清热、散结通络之功效。本课题以高血压肾损害与衰老肾脏相似的病理改变为基础，根据中医“异病同治”的理论，提出了“通过衰老相关的SIRT1途径，抑制高血压病理状态下肾脏固有细胞转分化及凋亡，减轻肾小球硬化和间质纤维化，是蝉花延缓高血压肾损害内在作用机制”的假说。我们以自发性高血压大鼠以及AngⅡ刺激下的肾脏固有细胞为研究对象，发现模型组SIRT1表达下调，应用蝉花及SIRT1激动剂白藜芦醇后，SIRT1异常表达被纠正；而且，上述治疗还可进一步使乙酰化P53蛋白表达降低、FOXO3a蛋白表达提高、自噬活性增强，TGF-β通路抑制，氧化应激水平下降。蝉花和白藜芦醇虽然对高血压大鼠血肌酐无明显影响，但是可以减轻肾脏固有细胞凋亡，使肾小管上皮细胞增值能力增强，同时，使SHR大鼠尿KIM-1、NGAL等指标好转，尿白蛋白排泄减少。提示蝉花可以通过上调SIRT1表达，进而抑制P53乙酰化水平、激活FOXO3a通路、增加自噬流量，延缓高血压肾损害。