No 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 2 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.

Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in genes that regulate activity of the renal sodium chloride cotransporter (NCC), including the kinases WNK1 and WNK4, and Cullin3 (Cul3) and KLHL3, members of a ring ubiquitin ligase complex. To examine the physiological roles of Cul3 and how mutations in it cause FHHt, we generated Cul3‐/‐ mice. An inducible system that disrupts Cul3 specifically along the entire nephron was used since complete Cul3 disruption is embryonic lethal. Western blots showed nearly complete absence of Cul3 in Cul3‐/‐ kidneys. Cul3‐/‐ mice displayed volume contraction, hypochloremia and alkalosis, and elevated plasma aldosterone. Blood pressure, measured by radiotelemetry, was similar in both groups on normal NaCl diet, but during NaCl restriction, Cul3‐/‐ mice displayed a progressive reduction in blood pressure. After 9 days, the 24h mean blood pressure pressure was 18 mmHg lower in Cul3‐/‐ mice. Expression of total and phospho‐NCC were slightly elevated in Cul3‐/‐ mice on normal diet, but dietary NaCl restriction did not cause their levels to increase to the same extent as it did in wild types. WNK4 expression was dramatically increased in Cul3‐/‐ mice on normal and low NaCl diets, while WNK1 and WNK3 were slightly elevated. In conclusion, these data suggest that loss of Cul3 activity along the nephron does not mimic FHHt, but leads to a mild salt‐wasting phenotype. Grant Funding Source: KO1 DK076617