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

• Published in: Laboratory investigation Vol. 98; no. 9; pp. 1237 - 1249
• Main Authors: Clotet-Freixas, Sergi, Soler, Maria Jose, Palau, Vanesa, Anguiano, Lidia, Gimeno, Javier, Konvalinka, Ana, Pascual, Julio, Riera, Marta
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01-09-2018; Nature Publishing Group US; Nature Publishing Group
• Subjects: 38/77; 42; 42/41; 631/443/272; 64; 64/60; 692/163/2743/137; 82/1; 82/29; 82/51; 96/2; ACE protein; ACE2; Angiotensin; Angiotensin II; Angiotensin II - administration & dosage; Angiotensin II - metabolism; Angiotensin-Converting Enzyme 2; Animals; Crosstalk; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - etiology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Dimorphism; Disease Progression; Enzymatic activity; Feedback, Physiological; Female; Females; Fibrosis; Gene expression; Hypertension; Hypertrophy; Kidney - metabolism; Kidney - pathology; Laboratory Medicine; Lesions; Male; Males; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephropathy; Pathology; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - deficiency; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Renin; Renin-Angiotensin System - physiology; Sex; Sex Characteristics; Sexual dimorphism
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-018-0084-x

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.
Sex and diabetes affect angiotensin-converting enzyme (ACE) and ACE2 expression and are key determinants of kidney disease progression. Here the authors demonstrate that there are sex differences in the severity of angiotensin II (ANGII)-hypertension and diabetic nephropathy, the activation of the renin-angiotensin system cascade, and the crosstalk between ACE and ACE2 in vivo. This work increases our understanding of the sex-specific role of ACE2 and ACE in diabetic nephropathy, reinforcing the necessity of individualized treatments.