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

Departments of 1 Medicine and 2 Pharmacology, University of California, and 3 Veterans Affairs San Diego Healthcare System, San Diego, California; 4 Department of Physiology, University of Tübingen, Tübingen; 5 Department of Biology, Chemistry, and Pharmacy, University of Berlin, Berlin, Germany; and 6 Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan Submitted 21 January 2009 ; accepted in final form 25 June 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 Thr 53 , 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 Thr 53 , Thr 58 , and Ser 71 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. with-no-lysine kinases; diuretic; epithelial sodium channel; intake; sodium chloride Address for reprint requests and other correspondence: V. Vallon, Division of Nephrology and Hypertension, Dept