Abstract

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.

Highlights

  • The Renin-Angiotensin-Aldosterone system is implicated in hypertension, cardiovascular and kidney diseases, where angiotensin II causes vasoconstriction (Harrison-Bernard, 2009) and induces reactive oxygen species (ROS) leading to vascular inflammation and injury (Nataraj et al, 1999a; Guzik et al, 2007a)

  • The activation of the ATTAC transgene was assessed from expression of the human caspase 8 coding sequence which does not share any homology with the endogenous mouse caspase 8 gene

  • The understanding of the role of cellular senescence was expanded to the pathophysiology of Alzheimer’s Disease, Type 1 Diabetes, Pulmonary Fibrosis, Osteoarthritis, Cardiovascular and Kidney Disease (Bhat et al, 2012; Palmer et al, 2015; Jeon et al, 2017; Álvarez et al, 2017; Shimizu and Minamino, 2019) whose prognosis is influenced by emerging vascular damage

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Summary

Introduction

The Renin-Angiotensin-Aldosterone system is implicated in hypertension, cardiovascular and kidney diseases, where angiotensin II causes vasoconstriction (Harrison-Bernard, 2009) and induces reactive oxygen species (ROS) leading to vascular inflammation and injury (Nataraj et al, 1999a; Guzik et al, 2007a). One cellular effect of ROS signaling is the induction of senescence that culminates in cell cycle arrest (Childs et al, 2015) and is associated with the upregulation of cell cycle proteins (p16Ink4a, p15Ink4b, p21CIP1). When Rb is hyperphosphorylated by cyclin-dependent kinases 4/ 6 (CDK4/6), it can dissociate from E2F which allows for transcription of S phase genes and lead to progression of the cell cycle (Zhang et al, 2000). If p16 is expressed it can inhibit CDK4/6 which leads to Rb not becoming phosphorylated and staying bound to E2F causing transcriptional repression of cell cycle genes and leading to cellular senescence (Fischer and Muller, 2017)

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