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

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, alpha-epithelial Na+ channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, gamma-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 (10-18 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 gamma-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.

Automated summary

The study using the 5/6 nephrectomy rat model found that spironolactone was effective in reducing hypertension in the high-salt diet group, while targeting aldosterone, the mineralocorticoid receptor, and especially angiotensin II in the normal-salt diet group could lower blood pressure.