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Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade

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Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. / Chiga, Motoko; Rafiqi, Fatema H.; Alessi, Dario R.; Sohara, Eisei; Ohta, Akihito; Rai, Tatemitsu; Sasaki, Sei; Uchida, Shinichi.

In: Journal of Cell Science, Vol. 124, No. 9, 01.05.2011, p. 1391-1395.

Research output: Contribution to journalArticle

Harvard

Chiga, M, Rafiqi, FH, Alessi, DR, Sohara, E, Ohta, A, Rai, T, Sasaki, S & Uchida, S 2011, 'Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade' Journal of Cell Science, vol 124, no. 9, pp. 1391-1395.

APA

Chiga, M., Rafiqi, F. H., Alessi, D. R., Sohara, E., Ohta, A., Rai, T., Sasaki, S., & Uchida, S. (2011). Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. Journal of Cell Science, 124(9), 1391-1395doi: 10.1242/jcs.084111

Vancouver

Chiga M, Rafiqi FH, Alessi DR, Sohara E, Ohta A, Rai T et al. Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. Journal of Cell Science. 2011 May 1;124(9):1391-1395.

Author

Chiga, Motoko; Rafiqi, Fatema H.; Alessi, Dario R.; Sohara, Eisei; Ohta, Akihito; Rai, Tatemitsu; Sasaki, Sei; Uchida, Shinichi / Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade.

In: Journal of Cell Science, Vol. 124, No. 9, 01.05.2011, p. 1391-1395.

Research output: Contribution to journalArticle

Bibtex - Download

@article{ad33c97f3881472b87e006350b168209,
title = "Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade",
author = "Motoko Chiga and Rafiqi, {Fatema H.} and Alessi, {Dario R.} and Eisei Sohara and Akihito Ohta and Tatemitsu Rai and Sei Sasaki and Shinichi Uchida",
year = "2011",
volume = "124",
number = "9",
pages = "1391--1395",
journal = "Journal of Cell Science",
issn = "0021-9533",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade

A1 - Chiga,Motoko

A1 - Rafiqi,Fatema H.

A1 - Alessi,Dario R.

A1 - Sohara,Eisei

A1 - Ohta,Akihito

A1 - Rai,Tatemitsu

A1 - Sasaki,Sei

A1 - Uchida,Shinichi

AU - Chiga,Motoko

AU - Rafiqi,Fatema H.

AU - Alessi,Dario R.

AU - Sohara,Eisei

AU - Ohta,Akihito

AU - Rai,Tatemitsu

AU - Sasaki,Sei

AU - Uchida,Shinichi

PY - 2011/5/1

Y1 - 2011/5/1

N2 - <p>We recently reported increased phosphorylation of the NaCl cotransporter (NCC) in Wnk4(D561A/+) knock-in mice, an ideal model of the human hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). Although previous in vitro studies had suggested the existence of a phosphorylation cascade involving the WNK, OSR1 and SPAK kinases, whether the WNK-OSR1/SPAK cascade is in fact fully responsible for NCC phosphorylation in vivo and whether the activation of this cascade is the sole mediator of PHAII remained to be determined. To clarify these issues, we mated the Wnk4(D561A/+) knock-in mice with Spak and Osr1 knock-in mice in which the T-loop threonine residues in SPAK and OSR1 (243 and 185, respectively) were mutated to alanine to prevent activation by WNK kinases. We found that NCC phosphorylation was almost completely abolished in Wnk4(D561A/+)Spak(T243A/T243A)Osr1(T185A/+) triple knock-in mice, clearly demonstrating that NCC phosphorylation in vivo is dependent on the WNK-OSR1/SPAK cascade. In addition, the high blood pressure, hyperkalemia and metabolic acidosis observed in Wnk4(D561A/+) mice were corrected in the triple knock-in mice. These results clearly establish that PHAII caused by the WNK4 D561A mutation is dependent on the activation of the WNK-OSR1/SPAK-NCC cascade and that the contribution of other mechanisms to PHAII (independent of the WNK-OSR1/SPAK cascade) could be minimal.</p>

AB - <p>We recently reported increased phosphorylation of the NaCl cotransporter (NCC) in Wnk4(D561A/+) knock-in mice, an ideal model of the human hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). Although previous in vitro studies had suggested the existence of a phosphorylation cascade involving the WNK, OSR1 and SPAK kinases, whether the WNK-OSR1/SPAK cascade is in fact fully responsible for NCC phosphorylation in vivo and whether the activation of this cascade is the sole mediator of PHAII remained to be determined. To clarify these issues, we mated the Wnk4(D561A/+) knock-in mice with Spak and Osr1 knock-in mice in which the T-loop threonine residues in SPAK and OSR1 (243 and 185, respectively) were mutated to alanine to prevent activation by WNK kinases. We found that NCC phosphorylation was almost completely abolished in Wnk4(D561A/+)Spak(T243A/T243A)Osr1(T185A/+) triple knock-in mice, clearly demonstrating that NCC phosphorylation in vivo is dependent on the WNK-OSR1/SPAK cascade. In addition, the high blood pressure, hyperkalemia and metabolic acidosis observed in Wnk4(D561A/+) mice were corrected in the triple knock-in mice. These results clearly establish that PHAII caused by the WNK4 D561A mutation is dependent on the activation of the WNK-OSR1/SPAK-NCC cascade and that the contribution of other mechanisms to PHAII (independent of the WNK-OSR1/SPAK cascade) could be minimal.</p>

KW - Blood pressure

KW - NaCl cotransporter

KW - WNK

KW - OSR1

KW - SPAK

U2 - 10.1242/jcs.084111

DO - 10.1242/jcs.084111

M1 - Article

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 9

VL - 124

SP - 1391

EP - 1395

ER -

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