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.
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
Submitter: Ariela Benigni | firstname.lastname@example.org
Mario Negri Institute for Pharmacological Research
Published November 11, 2009
In response to the letter from Dr. Amorena, we offer the following as clarification.
We are grateful to Dr. Amorena and his colleagues for their interest in our study.
Submitter: Carlos Amorena | email@example.com
Authors: Moretta R., García-Gras E., Tiscornia G., Argenziano M., Potilinski C., Siciliano E.
Published November 2, 2009
We have read the paper “Disruption of the Ang II type 1 receptor promotes longevity in mice” (JCI,2009,119:524-530) by Benigni et al. We think that there are points in this paper that deserve consideration.
The first result is presented ambiguously. The text reads: “At 29 months, when all wild-type animals died, 17 AT1a-deficient mice (85%) were still alive. These remaining mice lived for an additional 7 months.” However from Figure 1 we see that the remaining 17 mice were not alive at month 36. Furthermore, there is no indication as to whether the mice used to determine life span died spontaneously or were sacrificed when death appeared imminent. The second option is actually mentioned for other experiments in the methods section, but there is no reference to the criteria used to determine imminent death. In the list of signs that point to the proximity of death used by Jackson laboratory (http://research.jax.org/faculty/harrison/ger1vLifespan1.html) each one of them emphasize the external bad condition of mice. Assuming that this list of signs was used, it is remarkable that the internal organs of the AT1a-/- mice were in such good conditions as it is depicted. One could wonder what were the animals dying of.
Another subject that deserves comment is related to the differences the authors observed between WT and AT1a-/- mice in regard to cardiac hypertrophy. Even though it is not reported, we can reason that if body weight didn’t change (Figure 2A) and neither did heart weight/body weight ratio (Figure 3A), heart weight should remain constant between the two strains. Plus, the number of myocytes is also constant (Figure 3B). Then, how come is it possible that crossectional area of cardiomyocytes (Figures 3C) and interstitial collagen (Figure 3D) are statistically different? We wonder where the surplus mass originated in the larger fibers is placed. But this remarkable find isn’t even discussed.
Figure 4 shows the histology of the aorta of WT and AT1a-/- mice. Relying on the size of the nuclei in wild type vs. AT1a-/-, it looks like the magnification of the aorta of the wild type differs from that of the AT1a-/- animals. We find this confusing, for it prevents the observer from comparing the photographs properly. The legend “Original magnification, 20X”, without a scale bar seems to imply that the magnification is the same in all cases. We thank the Journal for the opportunity to discuss this issue.