Extracellular K<sup>+</sup> rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl<sup>−</sup>‐dependent and independent mechanisms

Pentón, David; Czogalla, Jan; Wengi, Agnieszka; Himmerkus, Nina; Loffing‐Cueni, Dominique; Carrel, Monique; Rajaram, R; Staub, Olivier; Bleich, Markus; Schweda, Frank; Loffing, Johannes

doi:10.1113/jp272504

Cited by 93 publications

(137 citation statements)

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“…We infer that WNK1 is similarly increased by the inactivation of KLHL3, which then becomes phosphorylated and activated by the decrease in intracellular Cl − levels, increasing NCC activity [27]. A very recent study also suggests a Cl − and SPAK/OSR1-independent component [28], adding an additional layer of NCC regulation by extracellular K + . These mechanisms act in concert to reduce distal electrogenic Na + reabsorption by increasing NCC, preventing further renal K + loss but promoting hypertension.…”

Section: Discussionmentioning

confidence: 96%

Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3

Ishizawa

Loffing

et al. 2016

Biochemical and Biophysical Research Communications

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Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K+ secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K+ intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K+-mediated activation of Na-Cl cotransporter (NCC) in the kidney. In the distal convoluted tubules of mice eating a low-K+ diet, we found increased KLHL3 phosphorylation at S433 (KLHL3S433-P), a modification that impairs WNK binding, and also reduced total KLHL3 levels. These changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1-related proline-alanine-rich protein kinase) and OSR1 (oxidative stress-responsive 1), resulting in NCC phosphorylation and its accumulation at the plasma membrane. Increased phosphorylation of S433 was explained by increased levels of active, phosphorylated protein kinase C (but not protein kinase A), which directly phosphorylates S433. Moreover, in HEK cells expressing KLHL3 and WNK4, we showed that the activation of protein kinase C by phorbol 12-myristate 13-acetate induces KLHL3S433-P and increases WNK4 levels by abrogating its ubiquitination. These data demonstrate the role of KLHL3 in low-K+-mediated induction of NCC; this physiologic adaptation reduces distal electrogenic Na+ reabsorption, preventing further renal K+ loss but promoting increased blood pressure.

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Section: Discussionmentioning

confidence: 96%

Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3

Ishizawa

Loffing

et al. 2016

Biochemical and Biophysical Research Communications

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“…Both mechanisms ultimately result in a loss of WNK ubiquitylation and degradation [17]. The findings that these mutations also cause FHHt strongly support the idea that both WNK1 and WNK4 activate NCC [15, 19, 73]. Further, knock-in mice with FHHt-like mutations in KLHL3 [R528H] have been reported to have an increased abundance of WNK4 proteins and increased NCC activity.…”

Section: Cul3–klhl3 As Upstream Regulators Of Wnk Kinasesmentioning

confidence: 88%

WNK signalling pathways in blood pressure regulation

Murthy

Kurz

O’Shaughnessy

2016

Cell. Mol. Life Sci.

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Hypertension (high blood pressure) is a major public health problem affecting more than a billion people worldwide with complications, including stroke, heart failure and kidney failure. The regulation of blood pressure is multifactorial reflecting genetic susceptibility, in utero environment and external factors such as obesity and salt intake. In keeping with Arthur Guyton's hypothesis, the kidney plays a key role in blood pressure control and data from clinical studies; physiology and genetics have shown that hypertension is driven a failure of the kidney to excrete excess salt at normal levels of blood pressure. There is a number of rare Mendelian blood pressure syndromes, which have shed light on the molecular mechanisms involved in dysregulated ion transport in the distal kidney. One in particular is Familial hyperkalemic hypertension (FHHt), an autosomal dominant monogenic form of hypertension characterised by high blood pressure, hyperkalemia, hyperchloremic metabolic acidosis, and hypercalciuria. The clinical signs of FHHt are treated by low doses of thiazide diuretic, and it mirrors Gitelman syndrome which features the inverse phenotype of hypotension, hypokalemic metabolic alkalosis, and hypocalciuria. Gitelman syndrome is caused by loss of function mutations in the thiazide-sensitive Na/Cl cotransporter (NCC); however, FHHt patients do not have mutations in the SCL12A3 locus encoding NCC. Instead, mutations have been identified in genes that have revealed a key signalling pathway that regulates NCC and several other key transporters and ion channels in the kidney that are critical for BP regulation. This is the WNK kinase signalling pathway that is the subject of this review.

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“…4) (Terker et al 2015b, Ishizawa et al 2016. A recent study also reported that a Cl − -and SPAK/OSR1-independent pathway activates NCC in hypokalemia (Penton et al 2016).…”

Section: Mechanisms Regulating Ncc In Dct Cellsmentioning

confidence: 97%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

Shibata

2017

Journal of Endocrinology

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A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K + homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified the molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K + secretion, the two major effects of aldosterone. In particular, recent studies have demonstrated that mineralocorticoid receptor in intercalated cells is selectively regulated by phosphorylation, which prevents ligand binding and activation. Moreover, the ubiquitin ligase complex composed of Kelch-like 3 and Cullin 3 acts downstream of angiotensin II and plasma K + alterations, regulating Na-Cl cotransporter independently of aldosterone in distal convoluted tubule cells. These and other effects are integrated to produce appropriate kidney responses in a high-aldosterone state, and are implicated in fluid and electrolyte disorders in humans. This review summarizes the current knowledge on mechanisms modulating mineralocorticoid receptor and its downstream effectors in the distal nephron.

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Extracellular K⁺ rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl⁻‐dependent and independent mechanisms

Cited by 93 publications

References 40 publications

Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3

Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3

WNK signalling pathways in blood pressure regulation

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

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Extracellular K+ rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl−‐dependent and independent mechanisms

Cited by 93 publications

References 40 publications

Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3

Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3

WNK signalling pathways in blood pressure regulation

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

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Extracellular K⁺ rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl⁻‐dependent and independent mechanisms