Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis

Terker, Andrew S.; Zhang, Chong; Erspamer, Kayla J.; Gamba, Gerardo; Yang, Chao; Ellison, David H.

doi:10.1038/ki.2015.289

Cited by 220 publications

(262 citation statements)

References 47 publications

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“…Perhaps expression of CUL3-Δ9 in the vasculature on a heterozygote background might increase blood pressure to a greater degree than it did on a WT background (34). WNK4 and SPAK have been shown to localize to intracellular puncta in SPAK-KO mice (42) and following dietary K + restriction (43,44). The precise identity and composition of these puncta, and their role in regulation of NCC activity, is currently unknown.…”

Section: Resultsmentioning

confidence: 99%

“…Redistribution of WNK1, WNK4, and SPAK to larger intracellular puncta has been reported in several mouse models with lower plasma [K + ], including SPAK KOs (42,51,52), and mice fed low K + diets (43,44,51). Whether puncta form when mice are placed on a high [K + ] diet has not yet been reported, but they were observed in mice with targeted deletion of Cul3 exon 9, which have elevated plasma [K + ] (30).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Ferdaus¹,

Miller²,

Agbor³

et al. 2017

JCI Insight

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Ferdaus¹,

Miller²,

Agbor³

et al. 2017

JCI Insight

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“…39 In fact, WNK4, which is most highly expressed in the DCT, is uniquely chloride sensitive. 40 Figure 3). This occurs, although plasma aldosterone concentrations, which are thought to stimulate NCC in other conditions, 43 rise during hyperkalemia (see above).…”

Section: Mechanisms Of K + Secretionmentioning

confidence: 99%

Potassium and Its Discontents

Ellison

Terker

Gamba

2016

Journal of the American Society of Nephrology

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Hyperkalemia is common in patients with impaired kidney function or who take drugs that inhibit the renin-angiotensin-aldosterone axis. During the past decade, substantial advances in understanding how the body controls potassium excretion have been made, which may lead to improved standard of care for these patients. Renal potassium disposition is primarily handled by a short segment of the nephron, comprising part of the distal convoluted tubule and the connecting tubule, and regulation results from the interplay between aldosterone and plasma potassium. When dietary potassium intake and plasma potassium are low, the electroneutral sodium chloride cotransporter is activated, leading to salt retention. This effect limits sodium delivery to potassium secretory segments, limiting potassium losses. In contrast, when dietary potassium intake is high, aldosterone is stimulated. Simultaneously, potassium inhibits the sodium chloride cotransporter. Because more sodium is then delivered to potassium secretory segments, primed by aldosterone, kaliuresis results. When these processes are disrupted, hyperkalemia results. Recently, new agents capable of removing potassium from the body and treating hyperkalemia have been tested in clinical trials. This development suggests that more effective and safer approaches to the prevention and treatment of hyperkalemia may be on the horizon.

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“…4A). When leucine 322 is removed from (134) suggest that the sensitivity profile is probably WNK4 Ͼ WNK1 Ͼ WNK3.…”

Section: F137 Slc12 Cotransporters In the Kidneymentioning

confidence: 99%

Physiological role of SLC12 family members in the kidney

Bazúa‐Valenti

Castañeda‐Bueno

Gamba

2016

American Journal of Physiology-Renal Physiology

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The solute carrier family 12, as numbered according to Human Genome Organisation (HUGO) nomenclature, encodes the electroneutral cation-coupled chloride cotransporters that are expressed in many cells and tissues; they play key roles in important physiological events, such as cell volume regulation, modulation of the intracellular chloride concentration, and transepithelial ion transport. Most of these family members are expressed in specific regions of the nephron. The Na-K-2Cl cotransporter NKCC2, which is located in the thick ascending limb, and the Na-Cl cotransporter, which is located in the distal convoluted tubule, play important roles in salt reabsorption and serve as the receptors for loop and thiazide diuretics, respectively (Thiazide diuretics are among the most commonly prescribed drugs in the world.). The activity of these transporters correlates with blood pressure levels; thus, their regulation has been a subject of intense research for more than a decade. The K-Cl cotransporters KCC1, KCC3, and KCC4 are expressed in several nephron segments, and their role in renal physiology is less understood but nevertheless important. Evidence suggests that they are involved in modulating proximal tubule glucose reabsorption, thick ascending limb salt reabsorption and collecting duct proton secretion. In this work, we present an overview of the physiological roles of these transporters in the kidney, with particular emphasis on the knowledge gained in the past few years.

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Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis

Cited by 220 publications

References 47 publications

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Potassium and Its Discontents

Physiological role of SLC12 family members in the kidney

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