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

<jats:p> The Na-Cl cotransporter NCC is expressed in the distal convoluted tubule, activated by phosphorylation, and has been implicated in renal NaCl and K<jats:sup>+</jats:sup> homeostasis. The serum and glucocorticoid inducible kinase 1 (SGK1) contributes to renal NaCl retention and K<jats:sup>+</jats:sup> excretion, at least in part, by stimulating the epithelial Na<jats:sup>+</jats:sup> channel and Na<jats:sup>+</jats:sup>-K<jats:sup>+</jats:sup>-ATPase in the downstream segments of aldosterone-sensitive Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup> exchange. In this study we confirmed in wild-type mice (WT) that dietary NaCl restriction increases renal NCC expression and its phosphorylation at Thr<jats:sup>53</jats:sup>, Thr<jats:sup>58</jats:sup>, and Ser<jats:sup>71</jats:sup>, respectively. This response, however, was attenuated in mice lacking SGK1 ( Sgk1<jats:sup>−/−</jats:sup>), which may contribute to impaired NaCl retention in those mice. Total renal NCC expression and phosphorylation at Thr<jats:sup>53</jats:sup>, Thr<jats:sup>58</jats:sup>, and Ser<jats:sup>71</jats:sup> in WT were greater under low- compared with high-K<jats:sup>+</jats:sup> diet. This finding is consistent with a regulation of NCC to modulate Na<jats:sup>+</jats:sup> delivery to downstream segments of Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup> exchange, thereby modulating K<jats:sup>+</jats:sup> excretion. Dietary K<jats:sup>+</jats:sup>-dependent variation in renal expression of total NCC and phosphorylated NCC were not attenuated in Sgk1<jats:sup>−/−</jats:sup> mice. In fact, high-K<jats:sup>+</jats:sup> diet-induced NCC suppression was enhanced in Sgk1<jats:sup>−/−</jats:sup> mice. The hyperkalemia induced in Sgk1<jats:sup>−/−</jats:sup> mice by a high-K<jats:sup>+</jats:sup> diet may have augmented NCC suppression, thereby increasing Na<jats:sup>+</jats:sup> delivery and facilitating K<jats:sup>+</jats:sup> excretion in downstream segments of impaired Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup> exchange. In summary, changes in NaCl and K<jats:sup>+</jats:sup> intake altered NCC expression and phosphorylation, an observation consistent with a role of NCC in NaCl and K<jats:sup>+</jats:sup> 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. </jats:p>