Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1.
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.
Vallon
Volker
V
Division of Nephrology and Hypertension, Dept. of Medicine, Univ. of California San Diego and VA San Diego Healthcare System, 3350 La Jolla Village Dr. (9151 San Diego, CA 92161, USA. vvallon@ucsd.edu
Schroth
Jana
J
Lang
Florian
F
Kuhl
Dietmar
D
Uchida
Shinichi
S
D000450:Aldosterone / Q000097:blood; D000818:Animals; D004231:Diuresis; D006947:Hyperkalemia / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017419:Potassium, Dietary / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism*; D012694:Serine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism*; D013912:Threonine; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D017874:Immediate-Early Proteins; D017419:Potassium, Dietary; D017346:Protein Serine-Threonine Kinases; D011955:Receptors, Drug; D012694:Serine; D017673:Sodium Chloride, Dietary; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D013912:Threonine; D000099184:Serum-Glucocorticoid Regulated Kinases; C578875:Slc12a3 protein, mouse