Double Knockout of the Na+-Driven Cl-/HCO3--Exchanger and Na+/Cl- Cotransporter Induces Hypokalemia and Volume Depletion

作者：Sinning Anne; Radionov Nikita; Trepiccione Francesco; Lopez Cayuqueo Karen I; Jayat Maximilien; Baron Stephanie; Corniere Nicolas; Alexander R Todd; Hadchouel Juliette; Eladari Dominique; Huebner Christian A; Chambrey Regine^*

来源：Journal of the American Society of Nephrology, 2017, 28(1): 130-139.

DOI：10.1681/ASN.2015070734

We recently described a novel thiazide-sensitive electroneutral NaCI transport mechanism resulting from the parallel operation of the Cl-/HCO3- exchanger pendrin and the Na+-driven Cl-/2HCO(3)(-) exchanger (NDCBE) in beta-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na+ balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na+ balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na homeostasis and provide evidence that the Na+/Cl- cotransporter (NCC) compensated for the inactivation of NDCBE. To unmaskthe role of NDCBE, we generated Ndcbe/Ncdclouble-knockout (dKO) mice. On a normal salt diet, dKO and single-knockout mice exhibited similar activation of the renin-angiotensin-aldosterone system, whereas only dKO mice displayed a lower blood K concentration. Furthermore, dKO mice displayed upregulation of the epithelial sodium channel (ENaC) and the Ca2+-activated K+ channel BKCa. During NaCI depletion, only dKO mice developed marked intravascular volume contraction, despite dramatically increased renin activity. Notably, the increase in aldosterone levels expected on NaCI depletion was attenuated in dKO mice, and single-knockout and dKO mice had similar blood K+ concentrations under this condition. In conclusion, NDCBE is necessary for maintaining sodium balance and intravascular volume during salt depletion or NCC inactivation in mice. Furthermore, NDCBE has an important role in the prevention of hypokalemia. Because NCC and NDCBE are both thiazide targets, the combined inhibition of NCC and the NDCBE/pendrin system may explain thiazide-induced hypokalemia in some patients.

• 出版日期2017-1