Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy

Abstract

Angiotensin-converting enzyme (ACE) and ACE2 play a critical role in the renin-angiotensin system (RAS) by altering angiotensin II (ANGII) levels, thus governing its deleterious effects. Both enzymes are altered by sex and diabetes, and play an important role in the development of diabetic nephropathy (DN). Importantly, previous evidence in diabetic and ACE2-deficient (ACE2KO) males suggest a sex-dependent crosstalk between renal ACE and ACE2. In the present work, we aimed to study the sex-specific susceptibility to diabetes and direct infusion of ANGII in kidney disease progression, with a special focus on its link to ACE2 and ACE. In our mouse model, ANGII promoted hypertension, albuminuria, reduced glomerular filtration, and glomerular histological alterations. ANGII adverse effects were accentuated by diabetes and ACE2 deficiency, in a sex-dependent fashion: ACE2 deficiency accentuated ANGII-induced hypertension, albuminuria, and glomerular hypertrophy in diabetic females, whereas in diabetic males exacerbated ANGII-mediated glomerular hypertrophy, mesangial expansion, and podocyte loss. At the molecular level, ANGII downregulated renal ACE gene and enzymatic activity levels, as well as renin gene expression in ACE2KO mice. Interestingly, male sex and diabetes accentuated this effect. Here we show sex dimorphism in the severity of diabetes- and ANGII-related renal lesions, and demonstrate that ACE2- and ACE-related compensatory mechanisms are sex-specific. Supporting our previous findings, the modulation and ANGII-mediated crosstalk between ACE2 and ACE in DN progression was more evident in males. This work increases the understanding of the sex-specific role of ACE2 and ACE in DN, reinforcing the necessity of more personalized treatments targeting RAS.

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“…Results of animal studies demonstrated that tissue-specific regulation of ACE2 by sex hormones could contribute to sex-related differences in obesity-hypertension [18]. The modulation and angiotensin II level by ACE2 and ACE could partly explain the sex-specific susceptibility to diabetes and diabetic nephropathy [19]. Further in-depth mechanical studies are warranted to understand the sex-related dimorphism of COVID-19.…”

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“…Studies have found that ACE2 has three main functions. [5][6][7] First, ACE2 is a powerful negative regulator of RAS, balancing the multiple ACE functions. By targeting angiotensin II, ACE2 shows protective effects in the cardiovascular system and many other organs.…”

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“…In agreement with these results, it was shown that ACE2 expression is decreased in the tubules in human diabetic nephropathy [ 94 ]. The imbalance of the RAAS system in favor of AngII in the context of diabetes results in a more severe kidney damage in males than in females, which is even increased if ACE2 is downregulated [ 95 , 96 ].…”