Intrarenal ghrelin receptors regulate ENaC-dependent sodium reabsorption by a cAMP-dependent pathway

The main distal nephron segment sodium transporters are the distal tubule chlorothiazide-sensitive sodium chloride cotransporter (NCC) and the collecting duct amiloride-sensitive epithelial sodium channel (E Na C). The infusion of ghrelin into the renal interstitium stimulates distal nephron–dependent sodium reabsorption in normal rats, but the mechanism is unknown. Here we localize renal ghrelin receptors (GR) to the cortical collecting duct (CCD). Ghrelin significantly increased phosphorylated serum/glucocorticoid-regulated kinase-1 (pSGK 1 ), a major upstream signaling intermediate regulating E Na C. To test whether increased apical membrane αE Na C induced the antinatriuresis, ghrelin was infused in the presence of acute and chronic amiloride, a selective inhibitor of E Na C. In the presence of amiloride, renal interstitial ghrelin failed to reduce urine sodium excretion, suggesting that ghrelin-induced sodium reabsorption is dependent on intact E Na C activity. While the main sodium transporter of the CCD is E Na C, NCC is also present. In response to renal interstitial ghrelin infusion, neither total nor phosphorylated NCC levels are altered. Ghrelin-induced sodium reabsorption persisted in the presence of chlorothiazide (selective inhibitor of NCC), indicating that intact NCC activity is not necessary for ghrelin-induced antinatriuresis. Finally, renal interstitial ghrelin infusion significantly increased interstitial cAMP levels and adenylyl cyclase blockade abolished ghrelin-induced antinatriuresis. Thus, GRs expressed in the CCD regulate sodium reabsorption by cAMP-induced trafficking of E Na C to the apical membrane.