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Disruption of the Ang II type 1 receptor promotes longevity in mice
Ariela Benigni, … , Thomas M. Coffman, Giuseppe Remuzzi
Ariela Benigni, … , Thomas M. Coffman, Giuseppe Remuzzi
Published February 9, 2009
Citation Information: J Clin Invest. 2009;119(3):524-530. https://doi.org/10.1172/JCI36703.
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Research Article Nephrology Article has an altmetric score of 41

Disruption of the Ang II type 1 receptor promotes longevity in mice

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Abstract

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 II type 1 receptors (AT1 and AT2). Here, we show that targeted disruption of the Agtr1a gene that encodes AT1A 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 II downregulated Sirt3 mRNA, and this effect was inhibited by an AT1 antagonist. These results demonstrate that disruption of AT1 promotes longevity in mice, possibly through the attenuation of oxidative stress and overexpression of prosurvival genes, and suggests that the Ang II/AT1 pathway may be targeted to influence life span in mammals.

Authors

Ariela Benigni, Daniela Corna, Carla Zoja, Aurelio Sonzogni, Roberto Latini, Monica Salio, Sara Conti, Daniela Rottoli, Lorena Longaretti, Paola Cassis, Marina Morigi, Thomas M. Coffman, Giuseppe Remuzzi

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Figure 6

AT1A deficiency prevents loss of mitochondria.

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AT1A deficiency prevents loss of mitochondria.
   
(A) Representative tr...
(A) Representative transmission electron micrographs of the ultrastructure of mouse proximal tubular cells obtained from resin-embedded kidney sections from young wild-type mice (2 months old), aged wild-type mice (26 to 29 months old), and Agtr1a–/– animals (26 to 30 months old). Scale bar: 1 μm. (B) The number of mitochondria per volume in proximal tubular cells in aged wild-type animals was decreased with respect to wild-type 2-month-old and Agtr1a–/– mice. Agtr1a–/– animals showed the same numerical density as wild-type 2-month-old animals. *P < 0.01 versus wild-type 2-month-old and Agtr1a–/– animals by ANOVA corrected with Bonferroni coefficient. Mean mitochondria volume evaluated on the same transmission electron micrographs through morphometrical analysis did not differ among groups. Data are mean ± SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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