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

Abstract

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. K E Y W O R D S angiotensin II, ENaC, female, potassium, proteinuria, sodium transport 2 of 12 | VEIRAS Et Al.

Impact of Casein- versus Grain-Based Diets on Rat Renal Sodium Transporters’ Abundance and Regulation

“…Taken together, the differences predict higher fractional reabsorption of sodium in proximal versus distal nephron of casein-chow fed rats at baseline (or lower fractional reabsorption in grain-versus casein-chow fed rats). 10 2) Similar 20-fold rise in aldosterone in both casein-chow fed (550 ± 61 to 12,949 ± 3,143 pg/ml plasma) and as reported recently for grain-chow fed rats, 10 3) Pressure-diuresis increased 2-fold in casein-chow fed (not shown) and 4-fold in grainchow fed rats. 10 Chow-dependent responses to AngII-HTN were evident all along the nephron, summarized in Fig.…”

“…Our study of the impact of AngII-HTN in female SDR fed grain-based chow was recently published. 10 The aim of this brief communication is to present, the effects of casein-based versus grain-based diets on sodium transporters' abundance and their regulation as a "cautionary tale" to investigators who, like us, utilize both grain-and casein-based chows to study renal transporter regulation. potassium, www.envigo.com) list similar levels of constituents (listed as % weight in grain, casein, respectively): sodium (0.4, 0.3%) potassium (1% in both), protein (24, 18%), carbohydrates (58, 63%) and fat (5.2, 5.3%).…”

“…Minor differences in these and other constituents may impact kidney sodium transporter expression directly or secondarily. Methods, previously described in detail 10 and abstracted in legends, were applied uniformly over a period of several months by the same personnel to the casein-chow and grain-chow fed rat series. Rats in both series were infused with 400 ng/kg/min AngII via osmotic mini-pumps for 14 days (AngII-HTN) or sham treated (control).…”

Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

“…During chronic Ang II infusion, sodium and volume excretion was significantly reduced in α2A-adrenoceptor deficient mice compared to wildtype mice (Hering et al, 2020). This impaired natriuretic response was in part caused by an increased abundance of the cleaved epithelial sodium channel (ENaC)-alpha and -gamma subtypes, both markers for ENaC activation (Nguyen et al, 2013;Veiras et al, 2020). The role of α2-adrenoceptors in controlling natriuresis is still not fully understood, as it is hard to distinguish between α2-adrenoceptor-mediated effects and effects mediated by an increased renal sympathetic norepinephrine release.…”

“…Ang II treatment decreased cAMP/PKA signaling and, therefore, the phosphorylation at serin 552 leading to increased NHE3 activity (Crajoinas et al, 2016). In contrast, increased sympathetic norepinephrine release in long-term Ang II-dependent hypertension suppresses NHE3 abundance (Nguyen et al, 2013;Hering et al, 2020;Veiras et al, 2020). This suppression of NHE3 is a compensatory natriuretic mechanism of the kidney to regulate blood pressure in chronic hypertension and override the stimulatory effect of Ang II on NHE3 (Mcdonough, 2010;Mcdonough and Nguyen, 2015).…”