Abstract
The mechanism by which chronic metabolic acidosis (CMA) regulates sodium (Na+)-chloride (Cl−) cotransporter (NCC) in the renal distal convoluted tubules remains unexplored. We examined the role of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and with-no-lysine kinase 4 (WNK4) on expression of NCC in mouse models of CMA. CMA was induced by NH4Cl in wild type mice (WTA mice), SPAK, and WNK4 knockout mice. The quantities of Ncc mRNA, expression of total NCC, phosphorylated (p)-NCC, SPAK and WNK4 in the kidneys as well as NCC inhibition with hydrochlorothiazide and Na+ balance were evaluated. Relative to WT mice, WTA mice had similar levels of Ncc mRNA, but increased expression of total and p-NCC, SPAK, and WNK4 and an exaggerated response to hydrochlorothiazide which could not be observed in SPAK or WNK4 knockout mice with CMA. In WTA mice, increased plasma renin activity, aldosterone and angiotensin II concentrations accompanied by a significantly negative Na+ balance. High Na+ diet abolished the enhanced NCC expression in WTA mice. Furthermore, an angiotensin II type 1 receptor blocker rather than a mineralocorticoid receptor antagonist exerted a marked inhibition on Na+ reabsorption and NCC phosphorylation in WTA mice. CMA increases WNK4-SPAK-dependent NCC phosphorylation and appears to be secondary to previous natriuresis with volume-dependent angiotensin II activation.
Highlights
Ducts[9,10,11]
We demonstrated that mice with NH4Cl-induced chronic metabolic acidosis (CMA) (WTA mice) had increased levels of total and p-Na+-Cl− cotransporter (NCC) and an exaggerated response to thiazide diuretics
In WTA mice, increased plasma renin activity (PRA) as well as elevated angiotensin II and aldosterone concentrations were accompanied by a significant negative Na+ balance and the enhanced NCC expression could be abolished by high Na+ diet suggestive of volume-dependent renin-angiotensin-aldosterone system (RAAS) activation
Summary
Ducts[9,10,11]. With respect to distal convoluted tubules (DCTs), Na+-Cl− cotransporter (NCC) responsible for 5% to 7% of the fine-tuning reabsorption of filtered Na+ has been reported to be changed in acidosis. The WNK4, as upstream of SPAK, can activate NCC by phosphorylating SPAK18. WNK4 knockout mice exhibit Gitelman-like syndrome with significantly reduced expression of SPAK and NCC19. The WNK4-SPAK signaling appears to be a major pathway to mediate NCC activation. Hormones such as aldosterone, angiotensin II, insulin, and vasopressin have been shown to regulate this signal pathway[20]. We investigated whether NCC was activated and regulated through WNK4-SPAK pathway in CMA induced by exogenous NH4Cl administration in different mice including wild type (WT), SPAK, and WNK4 knockout mice. The results to be reported indicated that mice with CMA exhibited the NCC activation through WNK4-SPAK-dependent pathway mediated by salt depletion with an enhanced angiotensin II
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