Disruption of the Ang II type 1 receptor promotes longevity in mice
Disruption of the Ang II type 1 receptor promotes longevity in mice
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DOI：
10.1172/jci36703
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发表时间：
2009-03-01
影响因子：
15.9
通讯作者：
Remuzzi, Giuseppe
中科院分区：
文献类型：
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作者：
Benigni, Ariela;Corna, Daniela;Remuzzi, Giuseppe
肾素-血管紧张素系统在人类高血压的病因学以及心脏和肾脏疾病的病理生理学中起作用。Ang II是该系统的中心产物，并通过Ang 11 1型受体（AT和AT（2））参与调节免疫应答、炎症、细胞生长和增殖。在这里，我们表明，有针对性地破坏编码AT（1A）的Agtr 1a基因，可显著延长小鼠的寿命。Agtr 1a（-/-）小鼠的心脏和血管损伤较少，这些小鼠的多个器官显示出比野生型小鼠更少的氧化损伤。长寿表型与肾脏中线粒体数量的增加和促生存基因烟酰胺磷酸核糖转移酶（Nampt）和沉默调节蛋白3（Sirt 3）的上调相关。在培养的肾小管上皮细胞中，Ang H下调Sirt 3 mRNA，这种作用可被AT 1拮抗剂抑制。这些结果表明，AT（1）的破坏促进小鼠的寿命，可能通过减轻氧化应激和促生存基因的过表达，并表明Ang II/AT（1）途径可能是影响哺乳动物寿命的靶点。
The renin-angiotensin system plays a role in the etiology of hypertension and the pathophysiology of cardiac and renal diseases in humans. Ang II is the central product of this system and is involved in regulating immune responses, inflammation, cell growth, and proliferation by acting through Ang 11 type 1 receptors (AT, and AT(2)). Here, we show that targeted disruption of the Agtr1a gene that encodes AT(1A) results in marked prolongation of life span in mice. Agtr1a(-/-) mice developed less cardiac and vascular injury, and multiple organs from these mice displayed less oxidative damage than wild-type mice. The longevity phenotype was associated with an increased number of mitochondria and upregulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney. In cultured tubular epithelial cells, Ang H downregulated Sirt3 mRNA, and this effect was inhibited by an AT, antagonist. These results demonstrate that disruption of AT(1) promotes longevity in mice, possibly through the attenuation of oxidative stress and overexpression of prosurvival genes, and suggests that the Ang II/AT(1) pathway may be targeted to influence life span in mammals.