Senescent Cells Mediate the Harmful Effects of Angiotensin II
Angiotensin II is used in many mouse models to induce hypertension and tissue damage, thereby accelerating the progression of a range of age-related conditions, including atherosclerosis. Researchers here show that an increased burden of senescent cells mediates these effects of angiotensin II, and that clearing senescent cells prevents the harms caused by increased angiotensin II levels. The near ubiquity of cellular senescence as an important mechanism linking forms of lower level molecular damage and dysregulation of metabolism to the development of disease continues to be surprising, even now.
Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16Ink4a-Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16Ink4a-dependent senescent cells by administration of AP20187.
Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen, and brain tissues. In the kidneys increased expression of ATM, p15, and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys.
AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular, and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects. In conclusion, the low dose, prolonged angiotensin II exposure is associated with the induction of senescence in kidneys and the promotion of an inflammatory microenvironment through both secreted factors and immune cells. Endothelial cells appear to be a major cell type impacted. The elimination of senescent cells in the INK-ATTAC transgenic model prevents these effects of angiotensin II and reveals a novel pathophysiologic mechanism amenable to targeting by senolytic drugs in development.