Abstract
The renin-angiotensin-aldosterone system has an important role in the control of fluid homeostasis and BP during volume depletion. Dietary salt restriction elevates circulating angiotensin II (AngII) and aldosterone levels, increasing levels of the Cl-/HCO3- exchanger pendrin in β-intercalated cells and the Na+-Cl- cotransporter (NCC) in distal convoluted tubules. However, the independent roles of AngII and aldosterone in regulating these levels remain unclear. In C57BL/6J mice receiving a low-salt diet or AngII infusion, we evaluated the membrane protein abundance of pendrin and NCC; assessed the phosphorylation of the mineralocorticoid receptor, which selectively inhibits aldosterone binding in intercalated cells; and measured BP by radiotelemetry in pendrin-knockout and wild-type mice. A low-salt diet or AngII infusion upregulated NCC and pendrin levels, decreased the phosphorylation of mineralocorticoid receptor in β-intercalated cells, and increased plasma aldosterone levels. Notably, a low-salt diet did not alter BP in wild-type mice, but significantly decreased BP in pendrin-knockout mice. To dissect the roles of AngII and aldosterone, we performed adrenalectomies in mice to remove aldosterone from the circulation. In adrenalectomized mice, AngII infusion again upregulated NCC expression, but did not affect pendrin expression despite the decreased phosphorylation of mineralocorticoid receptor. By contrast, AngII and aldosterone coadministration markedly elevated pendrin levels in adrenalectomized mice. Our results indicate that aldosterone is necessary for AngII-induced pendrin upregulation, and suggest that pendrin contributes to the maintenance of normal BP in cooperation with NCC during activation of the renin-angiotensin-aldosterone system by dietary salt restriction.
Highlights
The kidney maintains systemic fluid homeostasis predominantly through the reabsorption of filtered NaCl via specialized electrolyte transport mechanisms in different nephron segments
Activation of renin-angiotensinaldosterone system (RAAS) by NaCl Restriction Increases Pendrin and Decreases pMR-S843 Levels During volume depletion, the activated RAAS contributes to maintaining fluid volume through NaCl reabsorption
On the basis of the previous findings of Na+-Cl2 cotransporter (NCC) upregulation in PDS2/2 mice with an LS diet,[18] our results suggest that activation of pendrin contributed to maintaining normal BP in cooperation with NCC during volume depletion with an LS diet, in contrast to the small role of pendrin in the regulation of BP during volume repletion with an HS diet
Summary
Activation of RAAS by NaCl Restriction Increases Pendrin and Decreases pMR-S843 Levels During volume depletion, the activated RAAS contributes to maintaining fluid volume through NaCl reabsorption. To modulate intravascular volume by dietary salt intake, mice were fed either an HS (8% NaCl) or LS (0.03% NaCl) diet. NaCl restriction by an LS diet increased plasma renin activity (30.863.2 ng/ml per hour versus 18.861.8 ng/ml per hour; P=0.004) (Figure 1A) and plasma aldosterone concentrations (15136190 pg/ml versus 152648 pg/ml; P,0.001)
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