Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models

Author： Liu Zhen Xie Jian Wu Tao Truong Thao Auchus Richard J. Huang Chou-Long

Publisher： Oxford University Press

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.20, Iss.5, 2011-03, pp. : 855-866

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Abstract

WNK1 (with-no-lysine[K]-1) is a protein kinase of which mutations cause a familial hypertension and hyperkalemia syndrome known as pseudohypoaldosteronism type 2 (PHA2). Kidney-specific (KS) WNK1 is an alternatively spliced form of WNK1 kinase missing most of the kinase domain. KS-WNK1 downregulates the Na-Cl cotransporter NCC by antagonizing the effect of full-length WNK1 when expressed in Xenopus oocytes. The physiological role of KS-WNK1 in the regulation of NCC and potentially other Na transporters in vivo is unknown. Here, we report that mice overexpressing KS-WNK1 in the kidney exhibited renal Na wasting, elevated plasma levels of angiotensin II and aldosterone yet lower blood pressure relative to wild-type littermates. Immunofluorescent staining revealed reduced surface expression of total and phosphorylated NCC and the Na-K-2Cl cotransporter NKCC2 in the distal convoluted tubule and the thick ascending limb of Henle's loop, respectively. Conversely, mice with targeted deletion of exon 4A (the first exon for KS-WNK1) exhibited Na retention, elevated blood pressure on a high-Na diet and increased surface expression of total and phosphorylated NCC and NKCC2 in respective nephron segments. Thus, KS-WNK1 is a negative regulator of NCC and NKCC2 in vivo and plays an important role in the control of Na homeostasis and blood pressure. These results have important implications to the pathogenesis of PHA2 with WNK1 mutations.