Disruption of the Ang II type 1 receptor promotes longevity in mice.
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.
Benigni
Ariela
A
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, Bergamo, Italy. abenigni@marionegri.it
Corna
Daniela
D
Zoja
Carla
C
Sonzogni
Aurelio
A
Latini
Roberto
R
Salio
Monica
M
Conti
Sara
S
Rottoli
Daniela
D
Longaretti
Lorena
L
Cassis
Paola
P
Morigi
Marina
M
Coffman
Thomas M
TM
Remuzzi
Giuseppe
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation; D002149:Energy Intake; D006331:Heart Diseases / Q000235:genetics / Q000517:prevention & control; D008136:Longevity / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D045442:Rotarod Performance Test; D056566:Sirtuin 3; D037761:Sirtuins / Q000235:genetics; D015854:Up-Regulation; D014652:Vascular Diseases / Q000235:genetics / Q000517:prevention & control
D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D001786:Blood Glucose; D016207:Cytokines; D024101:Mitochondrial Proteins; C525046:Sirt3 protein, mouse; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D056566:Sirtuin 3; D037761:Sirtuins