Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases

Hadchouel, Juliette; Ellison, David H.; Gamba, Gerardo

doi:10.1146/annurev-physiol-021115-105431

Cited by 167 publications

(148 citation statements)

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“…In the kidney, the disease familial hyperkalemic hypertension (FHHt) exemplifies how studying such genes can lead to the elucidation of novel regulatory pathways. The discovery that mutations in the With-no-lysine [K] kinases (WNKs) Wnk1 and Wnk4 cause FHHt (1,2) and, more recently, that mutations in Cullin 3 (Cul3) (OMIM 614496, PHA2E) (3)(4)(5) and Kelch-like 3 (Klhl3) (4, 5) -components of an E3 ubiquitin ligase complex -also cause the disease has revealed a canonical pathway for the regulation of the Na + Cl -cotransporter (NCC). Along the distal convoluted tubule (DCT), NCC is activated by phosphorylation at several amino-terminal residues (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…These kinases are activated by WNK-mediated phosphorylation. FHHt-causing mutations in Wnk1 or Wnk4 increase abundances of WNK1 and WNK4 protein, increasing phosphorylation and activation of SPAK/OSR1 (1,2,10) and, hence, NCC phosphorylation. Increased NCC activity causes excessive Na + reabsorption that raises extracellular fluid volume and, thus, blood pressure.…”

Section: Introductionmentioning

confidence: 99%

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Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Ferdaus¹,

Miller²,

Agbor³

et al. 2017

JCI Insight

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Ferdaus¹,

Miller²,

Agbor³

et al. 2017

JCI Insight

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“…lowed by the appearance of hypertension [1][2][3][4] . All these abnormalities are corrected by the use of small doses of thiazide diuretics [4] .…”

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confidence: 99%

Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter

Bassat

Carmon²,

Hanukoglu³

et al. 2017

Nephron

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Background: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described. Methods: Clinical and genetic investigation of members of 2 families was performed, one with recessive FHHt, and the other, an expansion of a family with Q309R KLHL3 dominant mutation, previously reported by us. Urinary exosomal sodium chloride cotransporter (NCC) was measured. Results: A family with recessive FHHt caused by a new KLHL3 mutation, S553L, is described. This consanguineous Jewish family of Yemenite extraction, included 2 homozygous and 7 heterozygous affected subjects. Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation. In the recessive S553L family, homozygotes appeared to have increased urinary NCC abundance. Surprisingly, heterozygotes seemed to have also increased urinary NCC, though at an apparently lower degree. This was not accompanied by a clinical phenotype. Conclusions: A new recessive mutation in KLHL3 (S553L) was identified in FHHt. Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form. Unexpectedly, in the recessive disease, heterozygotes seemed to have increased urinary NCC as well, apparently not sufficient quantitatively to produce a clinical phenotype.

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“…Prior work has shown that WNK4 regulates diverse electrolyte flux mediators by kinase-dependent and independent mechanisms. The ability to regulate kinase activity independently of WNK4 level permits differential regulation of downstream targets (7).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to this kinase-dependent regulation of the Na-Cl contransporter, WNK4 also regulates the activity of other mediators of distal renal electrolyte transport, for example, inhibiting the K + channel ROMK (6). It thus appears that increased WNK4 activity can explain the increased Na-Cl reabsorption and hypertension seen in PHAII; the inhibition of ROMK can explain the inability to excrete K + , accounting for hyperkalemia (7). Inhibition of NCC activity can reverse both the hypertension and hyperkalemia seen with PHAII.…”

mentioning

confidence: 99%

Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4

Castañeda‐Bueno

Arroyo

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure. WNK4 phosphorylates the kinases SPAK (Ste20-related proline alanine-rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC). WNK4 levels are regulated by binding to Kelch-like 3, targeting WNK4 for ubiquitylation and degradation. Phosphorylation of Kelch-like 3 by PKC or PKA downstream of AngII or vasopressin signaling, respectively, abrogates binding. We tested whether these pathways also affect WNK4 phosphorylation and activity. By tandem mass spectrometry and use of phosphositespecific antibodies, we identified five WNK4 sites (S47, S64, S1169, S1180, S1196) that are phosphorylated downstream of AngII signaling in cultured cells and in vitro by PKC and PKA. Phosphorylation at S64 and S1196 promoted phosphorylation of the WNK4 kinase T-loop at S332, which is required for kinase activation, and increased phosphorylation of SPAK. Volume depletion induced phosphorylation of these sites in vivo, predominantly in the distal convoluted tubule. Thus, AngII, in addition to increasing WNK4 levels, also modulates WNK4 kinase activity via phosphorylation of sites outside the kinase domain.renin-angiotensin-aldosterone system | NCC | hypertension | renal electrolyte transport | distal convoluted tubule T he distal portion of the mammalian nephron plays a key role in water, electrolyte, and blood pressure homeostasis. Mutations that alter normal renal Na-Cl homeostasis in this nephron segment modulate blood pressure and result in diverse electrolyte abnormalities (1). One such rare Mendelian trait is Pseudohypoaldosteronism type II (PHAII, OMIM 145260), which is characterized by hypertension, hyperkalemia, and metabolic acidosis; these features can be corrected by low doses of thiazide diuretics, inhibitors of the Na-Cl cotransporter of the distal convoluted tubule (NCC).Genetic analysis of PHAII has revealed a previously unrecognized pathway that regulates blood pressure and electrolyte homeostasis in the distal nephron. Causative mutations have been found in four genes; two encode the serine-threonine kinases with-no-lysine 1 and 4 (WNK1 and WNK4) (2), and two encode Cullin 3 (CUL3) and Kelch-like 3 (KLHL3), components of an E3-RING ubiquitin ligase complex (3). At the time of the discovery of their causal relationship to this Mendelian disease, none of these proteins were known to play a role in electrolyte or blood pressure homeostasis. The biochemical mechanisms that link mutations to clinical phenoytpes are becoming understood. WNK4 is a Cl − -regulated kinase (4); when active, the kinase phosphorylates the kinases SPAK (Ste20-related proline alaninerich kinase) and OSR1 (oxidative stress responsive kinase), which in turn phosphorylate and activate the thiazide-sensitive Na-Cl cotransporter of the renal distal convoluted tubule (DCT). The phenotype of WNK4 knockout (WNK4-KO) mice recapitulates Gitelman syndrome (OMIM 263800), the mirror image of PHAII, sugg...

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Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases

Cited by 167 publications

References 126 publications

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter

Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4

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