Abstract
In Sprague Dawley rats, 2-week angiotensin II (AngII) infusion increases Na+ transporter abundance and activation from cortical thick ascending loop of Henle (TALH) to medullary collecting duct (CD) and raises blood pressure associated with a pressure natriuresis, accompanied by depressed Na+ transporter abundance and activation from proximal tubule (PT) through medullary TALH. This study tests the hypothesis that early during AngII infusion, before blood pressure raises, Na+ transporters’ abundance and activation increase all along the nephron. Male Sprague Dawley rats were infused via osmotic minipumps with a subpressor dose of AngII (200 ng/kg/min) or vehicle for 3 days. Overnight urine was collected in metabolic cages and sodium transporters’ abundance and phosphorylation were determined by immunoblotting homogenates of renal cortex and medulla. There were no significant differences in body weight gain, overnight urine volume, urinary Na+ and K+ excretion, or rate of excretion of a saline challenge between AngII and vehicle infused rats. The 3-day nonpressor AngII infusion significantly increased the abundance of PT Na+/H+ exchanger 3 (NHE3), cortical TALH Na-K-2Cl cotransporter 2 (NKCC2), distal convoluted tubule (DCT) Na-Cl cotransporter (NCC), and cortical CD ENaC subunits. Additionally, phosphorylation of cortical NKCC2, NCC, and STE20/SPS1-related proline–alanine-rich kinase (SPAK) were increased; medullary NKCC2 and SPAK were not altered. In conclusion, 3-day AngII infusion provokes PT NHE3 accumulation as well as NKCC2, NCC, and SPAK accumulation and activation in a prehypertensive phase before evidence for intrarenal angiotensinogen accumulation.
Highlights
The renin–angiotensin system (RAS) affects sodium balance, extracellular fluid volume, and renal and vascular resistance
Our previous analyses of chronic angiotensin II (AngII) infusion with accompanying hypertension demonstrated that a new homeostatic state was achieved that balanced AngII stimulation of Na+ transporters from the cortical thick ascending loop of Henle (TALH) to the collecting duct with hypertension-driven compensatory inhibition of Na+ transporters along the proximal tubule and medullary TALH, resulting in effective circulating volume homeostasis at normal levels
We asked whether short-term subpressor low-dose AngII without counteracting hypertension would stimulate proximal and TALH transporters including Na+/H+ exchanger 3 (NHE3) and Na-K-2Cl cotransporter 2 (NKCC2), and asked whether this low-dose AngII would stimulate distal transporters, including cortical NKCC, Na-Cl cotransporter (NCC), and ENaC without the augmented intrarenal RAS activation observed during 2-week AngII infusion
Summary
The renin–angiotensin system (RAS) affects sodium balance, extracellular fluid volume, and renal and vascular resistance. Acute ACE inhibition by captopril redistributes NHE3 from the body to the base of the microvilli and NaPi2 from villi into a subapical vesicular compartment (Leong et al 2006), and provokes acute NCC trafficking out of the plasma membrane (Sandberg et al 2007). In these studies, acute AngII stimulation or inhibition regulates Na+ transport via redistribution of transporters, rather than changing their total pool size or covalent modification by phosphorylation
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