Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport

TLDR

Aldosterone contributes to hypertension and cardiovascular disease, while low levels cause salt wasting; it activates mineralocorticoid receptors to upregulate ENaC and may also stimulate the thiazide‑sensitive Na⁺‑Cl⁻ cotransporter NCC. The study aimed to test whether nephron‑specific deletion of mineralocorticoid receptors would reveal direct regulation of ENaC and indirect effects on NCC. The authors generated mice with nephron‑specific deletion of mineralocorticoid receptors to evaluate distal salt transport mechanisms. MR‑knockout mice displayed salt wasting, hypotension, hyperkalemia, and impaired ENaC orientation, while NCC activity could be rescued by potassium restriction, demonstrating that mineralocorticoid receptors directly regulate ENaC and indirectly influence NCC through plasma potassium levels.

Abstract

Excess aldosterone is an important contributor to hypertension and cardiovascular disease. Conversely, low circulating aldosterone causes salt wasting and hypotension. Aldosterone activates mineralocorticoid receptors (MRs) to increase epithelial sodium channel (ENaC) activity. However, aldosterone may also stimulate the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC). Here, we generated mice in which MRs could be deleted along the nephron to test this hypothesis. These kidney-specific MR-knockout mice exhibited salt wasting, low BP, and hyperkalemia. Notably, we found evidence of deficient apical orientation and cleavage of ENaC, despite the salt wasting. Although these mice also exhibited deficient NCC activity, NCC could be stimulated by restricting dietary potassium, which also returned BP to control levels. Together, these results indicate that MRs regulate ENaC directly, but modulation of NCC is mediated by secondary changes in plasma potassium concentration. Electrolyte balance and BP seem to be determined, therefore, by a delicate interplay between direct and indirect mineralocorticoid actions in the distal nephron.