Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1

Vallon V, Schroth J, Lang F, Kuhl D, Uchida S. Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1. Am J Physiol Renal Physiol 297: F704-F712, 2009. First published July 1, 2009; doi:10.1152/ajprenal.00030.2009.- The Na-Cl cotransporter NCC is expressed in the distal convoluted tubule, activated by phosphorylation, and has been implicated in renal NaCl and K+ homeostasis. The serum and glucocorticoid inducible kinase 1 (SGK1) contributes to renal NaCl retention and K+ excretion, at least in part, by stimulating the epithelial Na+ channel and Na+-K+-ATPase in the downstream segments of aldosterone-sensitive Na+/K+ exchange. In this study we confirmed in wild-type mice (WT) that dietary NaCl restriction increases renal NCC expression and its phosphorylation at Thr53, Thr(58), and Ser(71), respectively. This response, however, was attenuated in mice lacking SGK1 (Sgk1(-/-)),which may contribute to impaired NaCl retention in those mice. Total renal NCC expression and phosphorylation at Thr53, Thr58, and Ser71 in WT were greater under low- compared with high-K+ diet. This finding is consistent with a regulation of NCC to modulate Na+ delivery to downstream segments of Na+/K+ exchange, thereby modulating K+ excretion. Dietary K+-dependent variation in renal expression of total NCC and phosphorylated NCC were not attenuated in Sgk1(-/-) mice. In fact, high-K+ diet-induced NCC suppression was enhanced in Sgk1(-/-) mice. The hyperkalemia induced in Sgk1(-/-) mice by a high- K+ diet may have augmented NCC suppression, thereby increasing Na+ delivery and facilitating K+ excretion in downstream segments of impaired Na+/K+ exchange. In summary, changes in NaCl and K+ intake altered NCC expression and phosphorylation, an observation consistent with a role of NCC in NaCl and K+ homeostasis. The two maneuvers dissociated plasma aldosterone levels from NCC expression and phosphorylation, implicating additional regulators. Regulation of NCC expression and phosphorylation by dietary NaCl restriction appears to involve SGK1.