TY - JOUR
T1 - Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway
AU - San-Cristobal, Pedro
AU - Pacheco-Alvarez, Diana
AU - Richardson, Ciaran
AU - Ring, Aaron M.
AU - Vazquez, Norma
AU - Rafiqi, Fatema H.
AU - Chari, Divya
AU - Kahle, Kristopher T.
AU - Leng, Qiang
AU - Bobadilla, Norma A.
AU - Hebert, Steven C.
AU - Alessi, Dario R.
AU - Lifton, Richard P.
AU - Gamba, Gerardo
PY - 2009/3/17
Y1 - 2009/3/17
N2 - Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K+ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K+ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K+ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K+ secretion.
AB - Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K+ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K+ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K+ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K+ secretion.
KW - Angiotensin II receptor
KW - Hypertension
KW - Distal convoluted tubule
KW - Salt reabsorption
KW - Thiazide
U2 - 10.1073/pnas.0813238106
DO - 10.1073/pnas.0813238106
M3 - Article
C2 - 19240212
SN - 0027-8424
VL - 106
SP - 4384
EP - 4389
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -