Angiotensin II infusion enhances renal aminopeptidase expression in female but not male mice

Sexual dimorphism in the intrarenal homeostasis of angiotensin (Ang) peptides may influence blood pressure control. Aminopeptidase A (APA) and aminopeptidase N (APN) catalyse the degradation of AngII and AngIII, respectively, but sex differences in their intrarenal expression are equivocal. The aim of this study was to determine if sex differences in renal APA and APN expression contribute to hypertensive kidney injury in mice. Mean arterial pressure (MAP) was measured via radiotelemetry in 5-month-old male and female C57bl/6 mice during baseline and 28-day infusion of vehicle (saline) or AngII (600 ng/kg/min s.c.; n=5-11/group). Glomerular filtration rate (transcutaneous FITC-sinistrin clearance) and protein excretion (24h metabolic cages) were assessed at baseline and end of AngII infusion. Kidneys were fixed for histological assessment of senescence-associated β-galactosidase (a cellular senescence marker), tubulointerstitial fibrosis, tubular dilation and glomerulosclerosis. APA and APN abundance in renal compartments were quantified via immunostaining (glomeruli, cortex, medulla) and Western blotting (cortical homogenates). All histological analyses were performed by a researcher blinded to experimental groups. Baseline MAP and GFR were similar between all groups. Pressor responsiveness to AngII was augmented in males compared to females (27 ± 4 mmHg vs 16 ± 2 mmHg respectively, on day 28; P=0.04). GFR was not affected by AngII infusion in either sex. AngII induced proteinuria (1.5-fold greater than vehicle; P=0.03), glomerular hypertrophy (P<0.0001 vs vehicle), tubular dilation (P<0.01 vs vehicle), tubulointerstitial fibrosis (P<0.001 vs vehicle) and tubular senescence (P<0.05 vs vehicle) in males but not females. Immunohistochemical studies revealed strong localisation of APA to the glomeruli, proximal tubule brush borders and medullary endothelial cells in all animals. AngII enhanced renal medullary expression of APA in both sexes (P=0.004 vs vehicle), but glomerular APA expression was enhanced in females only (P=0.02 vs vehicle). Total cortical APA expression, via Western blot and immunostaining, was not affected by AngII infusion in either sex. For all animals, immunohistochemical staining for APN was strong in the parietal epithelial cells, proximal tubule brush borders and medullary tubules. APN was not expressed in the glomerular tuft. AngII increased renal cortical and medullary APN expression in females (both P<0.01 vs vehicle) but not males. In summary, AngII induced hypertensive glomerular and tubular injury in male but not female mice. Enhancement of renal APA and APN expression in females may be a protective mechanism to reduce local AngII and AngIII levels, thereby counterbalancing Ang peptide-mediated effects. This work was funded by an ECR Transition Grant awarded to Dr Walton by the Foundation for High Blood Pressure Research. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.