TY - JOUR
T1 - SPAK differentially mediates vasopressin effects on sodium cotransporters
AU - Saritas, Turgay
AU - Borschewski, Aljona
AU - McCormick, James A.
AU - Paliege, Alexander
AU - Dathe, Christin
AU - Uchida, Shinichi
AU - Terker, Andrew
AU - Himmerkus, Nina
AU - Bleich, Markus
AU - Demaretz, Sylvie
AU - Laghmani, Kamel
AU - Delpire, Eric
AU - Ellison, David H.
AU - Bachmann, Sebastian
AU - Mutig, Kerim
PY - 2013/2/28
Y1 - 2013/2/28
N2 - Activation of the Na+-K+-2Cl-- cotransporter (NKCC2) and the Na+-Cl--cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conservedN-terminal threonine and serine residues, but the kinase pathways thatmediate this action of vasopressin are not well understood. Two homologous Ste20- like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor- specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.
AB - Activation of the Na+-K+-2Cl-- cotransporter (NKCC2) and the Na+-Cl--cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conservedN-terminal threonine and serine residues, but the kinase pathways thatmediate this action of vasopressin are not well understood. Two homologous Ste20- like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor- specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.
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U2 - 10.1681/ASN.2012040404
DO - 10.1681/ASN.2012040404
M3 - Article
C2 - 23393317
AN - SCOPUS:84874621317
SN - 1046-6673
VL - 24
SP - 407
EP - 418
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 3
ER -