Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, University of Virginia School of Medicine, Charlottesville, Virginia 22908-1414, USA.
Kidney Int. 2013 Sep;84(3):501-8. doi: 10.1038/ki.2013.187. Epub 2013 May 22.
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 (ENaC). 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 (pSGK1), a major upstream signaling intermediate regulating ENaC. To test whether increased apical membrane αENaC induced the antinatriuresis, ghrelin was infused in the presence of acute and chronic amiloride, a selective inhibitor of ENaC. In the presence of amiloride, renal interstitial ghrelin failed to reduce urine sodium excretion, suggesting that ghrelin-induced sodium reabsorption is dependent on intact ENaC activity. While the main sodium transporter of the CCD is ENaC, 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 ENaC to the apical membrane.
主要的远曲小管钠转运体是远曲小管氯噻嗪敏感的氯化钠共转运体（NCC）和集合管阿米洛利敏感的上皮钠通道（ENaC）。向肾间质输注促胃液素可刺激正常大鼠的远曲小管依赖的钠重吸收，但机制尚不清楚。在这里，我们将肾促胃液素受体（GR）定位在皮质集合管（CCD）。促胃液素显著增加了磷酸化血清/糖皮质激素调节激酶-1（pSGK1），这是调节 ENaC 的主要上游信号中间物。为了测试增加的顶端膜αENaC 是否诱导抗利尿作用，在急性和慢性阿米洛利（ENaC 的选择性抑制剂）存在的情况下，向肾间质输注促胃液素。在阿米洛利存在的情况下，肾间质促胃液素未能减少尿钠排泄，表明促胃液素诱导的钠重吸收依赖于完整的 ENaC 活性。虽然 CCD 的主要钠转运体是 ENaC，但 NCC 也存在。响应于肾间质促胃液素输注，总 NCC 或磷酸化 NCC 水平均未改变。氯噻嗪（NCC 的选择性抑制剂）存在时，促胃液素诱导的钠重吸收仍然存在，表明完整的 NCC 活性对于促胃液素诱导的抗利尿作用不是必需的。最后，肾间质促胃液素输注显著增加了间质 cAMP 水平，而腺苷酸环化酶阻断则消除了促胃液素诱导的抗利尿作用。因此，在 CCD 中表达的 GR 通过 cAMP 诱导 ENaC 向顶端膜的转运来调节钠重吸收。
