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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/F704    most recent 00030.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Vallon, V. Articles by Uchida, S. PubMed PubMed Citation Articles by Vallon, V. Articles by Uchida, S.

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

Departments of ¹Medicine and ²Pharmacology, University of California, and ³Veterans Affairs San Diego Healthcare System, San Diego, California; ⁴Department of Physiology, University of Tübingen, Tübingen; ⁵Department of Biology, Chemistry, and Pharmacy, University of Berlin, Berlin, Germany; and ⁶Department 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 Thr⁵³, Thr⁵⁸, and Ser⁷¹, 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.

with-no-lysine kinases; diuretic; epithelial sodium channel; intake; sodium chloride