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

Zhen Liu; Jian Xie; Tao Wu; Thao Truong; Richard J Auchus; Chou-Long Huang

doi:10.1093/hmg/ddq525

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

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

Zhen Liu, Jian Xie, Tao Wu, Thao Truong, Richard J Auchus and Chou-Long Huang

Human molecular genetics, Vol.20(5), pp.855-866

03/01/2011

DOI: 10.1093/hmg/ddq525

PMCID: PMC3033178

PMID: 21131289

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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.

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Title: Subtitle: Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models
Creators: Zhen Liu - and
Jian Xie - and
Tao Wu - The University of Texas Southwestern Medical Center
Thao Truong - and
Richard J Auchus - UT Southwestern Medical Center
Chou-Long Huang - and
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.20(5), pp.855-866
DOI: 10.1093/hmg/ddq525
PMID: 21131289
PMCID: PMC3033178
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: Oxford University Press
Language: English
Date published: 03/01/2011
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984094395802771

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