Electrolyte and transporter responses to angiotensin II induced hypertension in female and male rats and mice

Aim: Sexual dimorphisms are evident along the nephron: Females (F) exhibit higher ratios of renal distal to proximal Na⁺ transporters' abundance, greater lithium clearance (C_Li) more rapid natriuresis in response to saline infusion and lower plasma [K⁺] vs. males (M). During angiotensin II infusion hypertension (AngII-HTN) M exhibit distal Na⁺ transporter activation, lower proximal and medullary loop transporters, blunted natriuresis in response to saline load, and reduced plasma [K⁺]. This study aimed to determine whether responses of F to AngII-HTN mimicked those in M or were impacted by sexual dimorphisms evident at baseline. Methods: Sprague Dawley rats and C57BL/6 mice were AngII infused via osmotic minipumps 2 and 3 weeks, respectively, and assessed by metabolic cage collections, tail-cuff sphygmomanometer, semi-quantitative immunoblotting of kidney and patch-clamp electrophysiology. Results: In F rats, AngII-infusion increased BP to 190 mm Hg, increased phosphorylation of cortical NKCC2, NCC and cleavage of ENaC two to threefold, increased ENaC channel activity threefold and aldosterone 10-fold. K⁺ excretion increased and plasma [K⁺] decreased. Evidence of natriuresis in F included increased urine Na⁺ excretion and C_Li, and decreased medullary NHE3, NKCC2 and Na,K-ATPase abundance. In C57BL/6 mice, AngII-HTN increased abundance of distal Na⁺ transporters, suppressed proximal-medullary transporters and reduced plasma [K⁺] in both F and M. Conclusion: Despite baseline sexual dimorphisms, AngII-HTN provokes similar increases in BP, aldosterone, distal transporters, ENaC channel activation and K⁺ loss accompanied by similar suppression of proximal and loop Na⁺ transporters, natriuresis and diuresis in females and males.