Dietary salt modifies the blood pressure response to renin-angiotensin inhibition in experimental chronic kidney disease
Bovée, Dominique M; Uijl, Estrellita; Severs, David; Rubio-Beltrán, Eloisa; van Veghel, Richard; Maassen van den Brink, Antoinette; Joles, Jaap A; Zietse, Robert; Cuevas, Catherina A; Danser, A H Jan; Hoorn, Ewout J
(2021) American journal of physiology. Renal physiology, volume 320, issue 4, pp. F654 - F668
(Article)
Abstract
Chronic kidney disease contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared with sham rats, 5/6th
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nephrectomized rats had lower Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, Na+-Cl- cotransporter, α-epithelial Na+ channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, γ-ENaC, and Kir5.1 levels. These differences correlated with plasma renin, aldosterone, and/or K+. On a normal-salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 and -43 ± 9 mmHg). A high-salt diet caused skin Na+ and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation, and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat chronic kidney disease model, salt-sensitive hypertension develops with a selective increase in γ-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal-salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, whereas a high-salt diet causes more severe hypertension mediated through the mineralocorticoid receptor.NEW & NOTEWORTHY Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-angiotensin system inhibitor efficacy and specify the MR as a target in CKD.
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Keywords: Aldosterone/blood, Angiotensin II/pharmacology, Animals, Antihypertensive Agents/pharmacology, Blood Pressure/drug effects, Rats, Receptors, Mineralocorticoid/drug effects, Renal Insufficiency, Chronic/chemically induced, Renin-Angiotensin System/drug effects, Renin/pharmacology, Sodium Chloride, Dietary/metabolism, Spironolactone/pharmacology, potassium, 5/6th nephrectomy, aldosterone, renin, hypertension, Urology, Physiology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 1931-857X
Publisher: American Physiological Society
Note: Funding Information: This study is supported by Dutch Kidney Foundation Grant 14OK19 (to D.M.B. and E.J.H.). Publisher Copyright: © 2021 American Physiological Society. All rights reserved.
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