复旦大学新发现 肾损伤保护因子

【字体: 时间:2010年04月08日 来源:生物通

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  来自复旦大学附属医院郝传明教授领衔的研究小组近期发现了一种肾脏免疫氧化应激损伤的保护因子SIRT1,相关成果文章Sirt1 activation protects the mouse renal medulla from oxidative injury公布在最新一期的Journal of Clinical Investigation在线版上。

  

生物通报道,来自复旦大学附属医院郝传明教授领衔的研究小组近期发现了一种肾脏免疫氧化应激损伤的保护因子SIRT1,相关成果文章Sirt1 activation protects the mouse renal medulla from oxidative injury公布在最新一期的Journal of Clinical Investigation在线版上。

 

Sirt1(Sirtuin type 1)是依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的组蛋白脱乙酰酶, Sirtuins家族成员之一, 与细胞增殖、分化、衰老、凋亡和代谢密切相关。SIRT1能感受细胞中的能量水平,具有延缓细胞衰老、帮助细胞抵御外界应激和改善代谢的功能

 

在肾脏病的发病机制中,氧化应激起着重要作用。所谓氧化应激是由于人体新陈代谢过程中产生的“自由基”产生过多,超过了正常组织的抗氧化防御系统。年龄老化和能量过剩常导致氧化应激增加和机体的抗氧化功能下降,是引发肾脏病等多种慢性疾病的重要原因。肾脏(尤其是肾脏髓质)存在高水平的氧化应激,特别容易受到损害。

 

郝传明教授和他领导的国际团队通过一系列设计精巧的体外细胞和体内动物实验证实,SIRT1减少可加重氧化应激导致的肾脏损伤和肾脏的纤维化。重要的是如给予SIRT1激动剂可减轻由氧化应激引起的肾脏损伤。

 

该杂志同时配发了Nath教授的述评,认为该研究结果对我们认识肾脏对应激的反应有重要价值,并有可能对防治人类有关肾脏疾病提供新型治疗靶点,从而造福于广大慢性肾脏病患者。

(生物通 小茜)

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生物通推荐原文检索

J Clin Invest. 2010 Mar 24. pii: 41563. doi: 10.1172/JCI41563. [Epub ahead of print]

Sirt1 activation protects the mouse renal medulla from oxidative injury.

He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM.

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/- mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/- mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.

 

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