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Dual deficiency of angiotensin-converting enzyme-2 and Mas receptor enhances angiotensin II-induced hypertension and hypertensive nephropathy

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Item Type:Article
Title:Dual deficiency of angiotensin-converting enzyme-2 and Mas receptor enhances angiotensin II-induced hypertension and hypertensive nephropathy
Creators Name:Ni, J., Yang, F., Huang, X.R., Meng, J., Chen, J., Bader, M., Penninger, J.M., Fung, E., Yu, X.Q. and Lan, H.Y.
Abstract:Angiotensin-converting enzyme-2 (ACE2) and Mas receptor are the major components of the ACE2/Ang 1-7/Mas axis and have been shown to play a protective role in hypertension and hypertensive nephropathy individually. However, the effects of dual deficiency of ACE2 and Mas (ACE2/Mas) on Ang II-induced hypertensive nephropathy remain unexplored, which was investigated in this study in a mouse model of hypertension induced in either ACE2 knockout (KO) or Mas KO mice and in double ACE2/Mas KO mice by subcutaneously chronic infusion of Ang II. Compared with wild-type (WT) animals, mice lacking either ACE2 or Mas significantly increased blood pressure over 7-28 days following a chronic Ang II infusion (P < .001), which was further exacerbated in double ACE2/Mas KO mice (P < .001). Furthermore, compared to a single ACE2 or Mas KO mice, mice lacking ACE2/Mas developed more severe renal injury including higher levels of serum creatinine and a further reduction in creatinine clearance, and progressive renal inflammation and fibrosis. Mechanistically, worsen hypertensive nephropathy in double ACE2/Mas KO mice was associated with markedly enhanced AT1-ERK1/2-Smad3 and NF-κB signalling, thereby promoting renal fibrosis and renal inflammation in the hypertensive kidney. In conclusion, ACE2 and Mas play an additive protective role in Ang II-induced hypertension and hypertensive nephropathy. Thus, restoring the ACE2/Ang1-7/Mas axis may represent a novel therapy for hypertension and hypertensive nephropathy.
Keywords:ACE2, Ang II, Hypertension, Hypertensive Nephropathy, Mas, NF‐κB, TGF‐β/Smad3, Animals, Mice
Source:Journal of Cellular and Molecular Medicine
ISSN:1582-1838
Publisher:Wiley
Volume:24
Number:22
Page Range:13093-13103
Date:November 2020
Official Publication:https://doi.org/10.1111/jcmm.15914
PubMed:View item in PubMed

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