Renal and Brain Isoforms of WNK3 Have Opposite Effects on NCCT Expression

Glover, Mark; Zuber, Annie Mercier; O’Shaughnessy, Kevin M.

doi:10.1681/asn.2008050542

Cited by 46 publications

(64 citation statements)

References 25 publications

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“…There is no clear explanation for the discrepancies between our observations with WNK3-18b or WNK318bϩ22 and NCC and those of Glover et al (7). WNKs are complex kinases that are still poorly understood, but it seems that minimal disruption of their primary structures can prevent or switch their mode of action toward a particular target (13,23,29,32).…”

Section: C604contrasting

confidence: 99%

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Similar effects of all WNK3 variants on SLC12 cotransporters

Cruz-Rangel

Melo

Vázquez

et al. 2011

American Journal of Physiology-Cell Physiology

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kinase 3 (WNK3) is a member of a subfamily of serine/threonine kinases that modulate the activity of the electroneutral cation-coupled chloride cotransporters. WNK3 activates NKCC1/2 and NCC and inhibits the KCCs. Four splice variants are generated from the WNK3 gene. Our previous studies focused on the WNK3-18a variant. However, it has been suggested that other variants could have different effects on the cotransporters. Thus, the present study was designed to define the effects of all WNK3 variants on members of the SLC12 family. By RT-PCR from a fetal brain library, exons 18b and 22 were separately amplified and subcloned into the original WNK3-18a or catalytically inactive WNK3-D294A to obtain all four potential combinations with and without catalytic activity (18a, 18aϩ22, 18b, and 18bϩ22). The basal activity of the cotransporters and the effects of WNK3 isoforms were assessed in Xenopus laevis oocytes coinjected with each of the WNK3 variant cRNAs. In isotonic conditions, the basal activity of NCC and NKCC1/2 were increased by coinjection with any of the WNK3. The positive effects occurred even in hypotonic conditions, in which the basal activity of NKCC1 is completely prevented. Consistent with these observations, when expressed in hypotonicity, all KCCs were active, but in the presence of any of the WNK3 variants, KCC activity was completely reduced. That is, NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. We conclude that the effects of all WNK3 variants toward SLC12 proteins are similar.

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Section: C604contrasting

confidence: 99%

“…The activation of NCC by WNK3-18a has been corroborated by other groups (7,32). In the present study, we tested the effects of all potential WNK3 variants on the activity of these cotransporters.…”

Section: Effects Of Wnk3 Variants On the Sodium-coupled Chloride Cotrsupporting

confidence: 60%

Similar effects of all WNK3 variants on SLC12 cotransporters

Cruz-Rangel

Melo

Vázquez

et al. 2011

American Journal of Physiology-Cell Physiology

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“…WNK3 is expressed in the brain and the kidneys as differently spliced variants due to the presence or absence of exons 18a or 18b, as well as of exon 22. One study showed that while the renal WNK3 isoforms activate NCC, the brain isoforms actually inhibit the cotransporter (24). However, another study reported that all WNK3 variants displayed the same effect on all members of the SLC12 family, including NCC (13).…”

Section: Wnk3 Is a Powerful Activator Of Nccmentioning

confidence: 99%

Revisiting the NaCl cotransporter regulation by with-no-lysine kinases

Bazúa‐Valenti

Gamba

2015

American Journal of Physiology-Cell Physiology

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The renal thiazidesensitive Na ϩ -Cl Ϫ cotransporter (NCC) is the salt transporter in the distal convoluted tubule. Its activity is fundamental for defining blood pressure levels. Decreased NCC activity is associated with salt-remediable arterial hypotension with hypokalemia (Gitelman disease), while increased activity results in salt-sensitive arterial hypertension with hyperkalemia (pseudohypoaldosteronism type II; PHAII). The discovery of four different genes causing PHAII revealed a complex multiprotein system that regulates the activity of NCC. Two genes encode for with-no-lysine (K) kinases WNK1 and WNK4, while two encode for kelch-like 3 (KLHL3) and cullin 3 (CUL3) proteins that form a RING type E3 ubiquitin ligase complex. Extensive research has shown that WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and that WNKs modulate the activity of NCC by means of intermediary Ste20-type kinases known as SPAK or OSR1. The understanding of the effect of WNKs on NCC is a complex issue, but recent evidence discussed in this review suggests that we could be reaching the end of the dark ages regarding this matter.WNK4; distal tubule; ion transport; hypertension; diuretics THE INVITATION OF THE EPITHELIAL TRANSPORT GROUP to present the Steven Hebert Lecture in 2013 came as a very pleasant surprise since it gave me (G. Gamba) the opportunity to make a remembrance of one true scientist, with whom I had the privilege to be trained. I first met Steve at Harvard in the late 1980s when I was looking for a fellow position and he was an assistant professor of medicine. I was 27 and he was 42 years old. The day I met him in 1989 he explained to me his complicated tubular perfusion techniques, only to conclude by saying: "I am not going to do this anymore because next year I will pursue a transition from perfused tubules to expression cloning and molecular biology." One year later, with the trust and patience that characterized him as a mentor, there he was, putting such a risky and ambitious enterprise in the hands of two clinicians (Kevin Ho from Ohio and myself from Mexico) with no experience at all in molecular biology, one of whom could not even speak good English at the time. In three years we identified at the molecular level the cDNA encoding the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter (NCC) of the distal convoluted tubule (DCT) (21), the loop-diuretic sensitive Na (20) and the renal outer medulla potassium channel (ROMK) (28) of the thick ascending limb of Henle's loop and the calcium-sensing receptor (CaSR) from bovine parathyroid (6). Steven Hebert was a true visionary, with confidence enough to pursue areas of research that were considered high risk and controversial. He was always on the cutting edge.NCC cDNA was identified by expression cloning (Fig. 1) thanks to previous seminal works from Larry Renfro (59), David Ellison (17), and John Stokes (72) that revealed the functional characteristics of the cotransporter and the winter flounder urinary bladder as a unique source of mRNA for expression cloni...

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“…The phosphorylation of NCC is mediated by SPAK [79]; several WNKs interact with SPAK and therefore indirectly control the phoshorylation-step of NCC. Interactions between SPAK and WNK1 [79], WNK3 [34], and WNK4 [102] have been reported. However, the brain but not the kidney isoform of WNK3 can activate NCC and does so through a SPAKindependent mechanism [34].…”

Section: Kinasesmentioning

confidence: 99%

“…Interactions between SPAK and WNK1 [79], WNK3 [34], and WNK4 [102] have been reported. However, the brain but not the kidney isoform of WNK3 can activate NCC and does so through a SPAKindependent mechanism [34]. Two isoforms of SPAK have been identified, including full-length SPAK (FL-SPAK) and kidney-specific SPAK (KS-SPAK or SPAK2), of which the latter isoform has low expression levels in the DCT [73].…”

Section: Kinasesmentioning

confidence: 99%

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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Renal and Brain Isoforms of WNK3 Have Opposite Effects on NCCT Expression

Cited by 46 publications

References 25 publications

Similar effects of all WNK3 variants on SLC12 cotransporters

Similar effects of all WNK3 variants on SLC12 cotransporters

Revisiting the NaCl cotransporter regulation by with-no-lysine kinases

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

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