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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.
Highlights
Hypertensive nephropathy is a major complication of hypertension and is the main cause of chronic kidney disease (CKD) characterized by progressive renal fibrosis and inflammation.[1]
Accumulating evidence has shown that the pathogenic actions of the Ang I-converting enzyme (ACE)/Angiotensin II (Ang II)/Ang II type 1 receptor (AT1) axis can be countered by the angiotensin-converting enzyme 2 (ACE2)/Ang 1-7/Mas receptor (Mas) axis
We found that mice with a single or double deletion of ACE2 and Mas gene developed normally with a normal range of blood pressure, bodyweight and renal function
Summary
Hypertensive nephropathy is a major complication of hypertension and is the main cause of chronic kidney disease (CKD) characterized by progressive renal fibrosis and inflammation.[1]. KO mice were used after being backcrossed for 8 generations Both single- and double-gene KO mice were identified by genotyping with primers as described previously.[10,18] Hypertensive nephropathy was induced in WT, ACE2 KO, Mas KO and ACE2/ Mas double KO mice (male; 8-10 weeks of age; 20-25 g) by subcutaneous infusion of Ang II at a dose of 1.0 mg/kg per day or saline as the control for 28 days via osmotic mini-pumps (Model 2004; ALzet, California).[20,21] Blood pressure (BP) was measured by the tail-cuff method using the CODA non-invasive blood pressure system (Kent Scientific, Torrington, CT) in conscious mice according to the manufacturer's instructions. Twenty-four-hour urine was collected at day 28 after Ang II infusion for urinary protein measurement using the Quick StartTM Bradford Dye Reagent (Bio-Rad Laboratories, CA, USA). The creatinine clearance was calculated using the following formula: [urine creatinine (μmol/L) × 24 h urine volume (ml)]/[24 × 60 (min) × serum creatinine (μmol/L)]
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