Dietary salt modifies the blood pressure response to renin-angiotensin inhibition in experimental chronic kidney disease

Dominique M. Bovee, Estrellita Uijl, David Severs, Eloisa Rubio-Beltran, Richard van Veghel, Antoinette Maassen van den Brink, Jaap A. Joles, Robert Zietse, Catherina A. Cuevas, A. H. Jan Danser, Ewout J. Hoorn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)


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 nephrectomized rats had lower Na/H exchanger isoform 3, Na-K-2Cl cotransporter, Na-Cl cotransporter, a-epithelial Na channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, c-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 c-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 and 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.

Original languageEnglish
Pages (from-to)F654-F668
JournalAmerican Journal of Physiology-Renal Physiology
Issue number4
Publication statusPublished - 8 Apr 2021

Bibliographical 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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