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

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

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 8

Effect of Ang II on prosurvival genes in mouse cultured PTECs.

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Effect of Ang II on prosurvival genes in mouse cultured PTECs. (A) Ang I...
(A) Ang II downregulates Nampt and Sirt3 mRNA via AT1. After 24-hour incubation with serum-free DMEM, PTECs were incubated with candesartan (0.1 μM) or medium for 1 hour and then exposed to Ang II (1 μM) or medium (control) for 3 hours. The black column represents unstimulated cells maintained in medium (control) for 4 hours. Nampt and Sirt3 mRNA levels were evaluated by real-time PCR. Data are mean ± SD of 3 experiments. *P < 0.01 versus control, †P < 0.01 versus Ang II by ANOVA corrected with Bonferroni coefficient. (B) Nampt modulates Sirt3 gene transcription in response to Ang II. After 6 hour transfection with Nampt siRNA, cells were maintained in medium for 45 hours and then incubated 3 hours with Ang II. Data are mean ± SD of 3 experiments. *P < 0.01 versus control, ‡P < 0.01 versus siRNA control plus Ang II by Student’s t test for unpaired data (left panel) or ANOVA corrected with Bonferroni coefficient (right panel).