The angiotensin‐(1‐7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation

Abstract

Endothelial cell senescence is a hallmark of vascular aging that predisposes to vascular disease. We aimed to explore the capacity of the renin–angiotensin system (RAS) heptapeptide angiotensin (Ang)‐(1‐7) to counteract human endothelial cell senescence and to identify intracellular pathways mediating its potential protective action. In human umbilical vein endothelial cell (HUVEC) cultures, Ang II promoted cell senescence, as revealed by the enhancement in senescence‐associated galactosidase (SA‐β‐gal+) positive staining, total and telomeric DNA damage, adhesion molecule expression, and human mononuclear adhesion to HUVEC monolayers. By activating the G protein‐coupled receptor Mas, Ang‐(1‐7) inhibited the pro‐senescence action of Ang II, but also of a non‐RAS stressor such as the cytokine IL‐1β. Moreover, Ang‐(1‐7) enhanced endothelial klotho levels, while klotho silencing resulted in the loss of the anti‐senescence action of the heptapeptide. Indeed, both Ang‐(1‐7) and recombinant klotho activated the cytoprotective Nrf2/heme oxygenase‐1 (HO‐1) pathway. The HO‐1 inhibitor tin protoporphyrin IX prevented the anti‐senescence action evoked by Ang‐(1‐7) or recombinant klotho. Overall, the present study identifies Ang‐(1‐7) as an anti‐senescence peptide displaying its protective action beyond the RAS by consecutively activating klotho and Nrf2/HO‐1. Ang‐(1‐7) mimetic drugs may thus prove useful to prevent endothelial cell senescence and its related vascular complications.

Inflammation and Premature Ageing in Chronic Kidney Disease

“…Concluding the findings discussed above, treatment of the repressed NRF2 system in CKD can improve oxidative stress and mitochondrial function [125,149], inflammation [27,123,149], as well as premature ageing [122], in particular EVA [120,121].…”

“…Molecular markers of vascular senescence, that is, p16 INK4a and p21 Waf1/Cip1 , as well as cytokines of the SASP, are increased in NRF2-deficient mice compared to control mice [120]. Klotho also exerts some of its beneficial effects on EVA by activating the NRF2 pathway [121]. Furthermore, because testosterone ameliorates age-related renal fibrosis in mice via activation of NRF2 signaling [122], the effects of sex hormones and their supplementation in CKD also need attention.…”

Oxidative stress, telomeres and cellular senescence: What non-drug interventions might break the link?

“…The Mediterranean diet (MD) is rich in sources of bioactive compounds that are thought to play a role in protecting the organism against inflammation and other sources of oxidative stress [60]. This protective function may be achieved in part by activating detoxifying stress responses, which in vitro are known to ameliorate telomere shortening and senescence [85]. In vivo, the effect of the MD on telomere length has been examined in a relatively large RCT, which had been originally designed to investigate the effects of this diet on the primary prevention of cardiovascular disease.…”

Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

“…The down-regulation of ACE2 reduces the Ang-1,7 anti-oxidant activity that was found to activate Nrf2. 115,116 Nrf2 protects against hallmarks of severe COVID-19. It has anti-fibrotic effects on various organs including the lungs, 117 protects against lung injury and acute respiratory distress syndrome, 118 and endothelial damage, 75 .…”