Sex-specific ACE2 regulation contributes to female protection from Ang-[1–8]–induced hypertension in mice, as Ang-[1–8] reduced AT1R binding by 30% in WT females but increased it 1.2-fold in males.
Does ACE2 modulate Ang-[1-8]-induced hypertension and renin-angiotensin system regulation in a sex-specific manner in mice?
ACE2 regulation of the renin-angiotensin system is sex-specific, contributing to female protection from Ang-[1-8]-induced hypertension in a mouse model.
We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-1–8 (angiotensin 1–8)–induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-1–8 infusion. This sex difference was attenuated in ACE2 KO mice. Ang-1–8 infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of Ace2 abolished this effect. In contrast, Ang-1–8 infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-1–8 persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-1–10 (angiotensin 1–10), the precursor of Ang-1–8. Ang-1–8 infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-1-8 infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-1–8–induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.
Ji et al. (Mon,) conducted a other in Hypertension. Ang-[1-8] infusion and Ace2 deletion vs. Wild type vs Ace2 knockout; male vs female was evaluated on Mean arterial pressure and glomerular AT1R binding. Sex-specific ACE2 regulation contributes to female protection from Ang-[1–8]–induced hypertension in mice, as Ang-[1–8] reduced AT1R binding by 30% in WT females but increased it 1.2-fold in males.
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