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

Bazúa‐Valenti, Silvana; Gamba, Gerardo

doi:10.1152/ajpcell.00065.2015

Cited by 47 publications

(29 citation statements)

References 96 publications

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“…9 Chronic AngII regulation of NCC and its phosphorylation have been attributed to the stimulation of a WNK-SPAK kinase cascade. 10, 11 Indeed, our own studies show that renal cortical SPAK (Ste20/SPS-1 related proline-alanine rich kinase) is stimulated during chronic AngII infusion hypertension and that if intrarenal production of AngII is prevented, both the NCC and SPAK stimulation are blocked and the rise in blood pressure is blunted. 4, 8 …”

Section: Introductionmentioning

confidence: 91%

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

et al. 2016

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Ang II hypertension increases distal tubule Na-Cl cotransporter (NCC) abundance and phosphorylation (NCCp), as well as epithelial Na+ channel (ENaC) abundance and activating cleavage. Acutely raising plasma [K+] by infusion or ingestion provokes a rapid decrease in NCCp that drives a compensatory kaliuresis. The first aim tested whether acutely raising plasma [K+] with a single 3 hr 2% potassium meal would lower NCCp in Sprague Dawley rats after 14 days of AngII (400 ng/kg/min). The potassium-rich meal neither decreased NCCp nor increased K+ excretion. AngII infused rats exhibited lower plasma [K+] versus controls (3.6 ± 0.2 vs. 4.5 ± 0.1 mmol/L, p < 0.05) suggesting that Ang II mediated ENaC activation provokes K+ depletion. The second aim tested whether doubling dietary potassium intake from 1% (A1K) to 2% (A2K) would prevent K+ depletion during AngII infusion and, thus, prevent NCC accumulation. A2K fed rats exhibited normal plasma [K+] and 2-fold higher K+ excretion and plasma [aldosterone] versus A1K. In A1K rats, NCC, NCCpS71, and NCCpT53 abundance increased 1.5- to 3-fold versus controls (p< 0.05). The rise in NCC and NCCp abundance was prevented in the A2K rats, yet blood pressure did not significantly decrease. ENaC subunit abundance and cleavage increased 1.5- to 3-fold in both A1K and A2K; ROMK abundance was unaffected by Ang II or dietary K+. In summary, the accumulation and phosphorylation of NCC seen during chronic AngII infusion hypertension is likely secondary to potassium deficiency driven by ENaC stimulation.

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Section: Introductionmentioning

confidence: 91%

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

et al. 2016

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“…Because WNK4 is also a key regulator of distal tubular membrane abundance of the Na + :Cl − cotransporter NCC [68], the finding that FGF23 signaling activates WNK4 in distal tubular epithelium prompted us to examine FGF23-induced changes in renal sodium handling. NCC is a key molecule for distal tubular sodium and chloride reabsorption, and sodium reabsorption in the distal nephron is mainly regulated through NCC and the epithelial sodium channel ENaC.…”

Section: Distal Tubular Calcium and Sodium Transportmentioning

confidence: 99%

FGF23-Klotho signaling axis in the kidney

Erben

Andrukhova

2017

Bone

136

110

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Fibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium. In proximal renal tubules, FGF23 suppresses phosphate reabsorption by a Klotho dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1), leading to phosphorylation of the scaffolding protein Na/H exchange regulatory cofactor (NHERF)-1 and subsequent internalization and degradation of sodium-phosphate cotransporters. In distal renal tubules, FGF23 augments calcium and sodium reabsorption by increasing the apical membrane expression of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC through a Klotho dependent activation of with-no-lysine kinase-4 (WNK4). In proximal and distal renal tubules, FGF receptor-1 is probably the dominant FGF receptor mediating the effects of FGF23 by forming a complex with membrane-bound Klotho in the basolateral membrane. The newly described sodium- and calcium-conserving functions of FGF23 may have major implications for the pathophysiology of diseases characterized by chronically increased circulating FGF23 concentrations such as chronic kidney disease.

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“…WNK phosphorylates and activates SPAK or OSR which in turn stimulates NCC activity by phosphorylation [54;56]. Gain-of-function mutations of WNK1 and WNK4 are responsible for increasing NCC activity in the DCT thereby causing familial hyperkalemic hypertension [57;58]. Thus, WNK-SPAK-mediated NCC phosphorylation plays a key role in the regulation of K excretion and K homeostasis.…”

Section: Expression Of Kir41 Along the Nephron Segmentsmentioning

confidence: 99%

Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity

Wang

2016

Current Opinion in Nephrology and Hypertension

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Purpose of Review Renal potassium (K) secretion plays a key role in maintaining K homeostasis. The classic mechanism of renal K secretion is focused on the connecting tubule (CNT) and cortical collecting duct (CCD) in which K is uptaken by basolateral Na-K-ATPase and it is secreted into lumen by apical ROMK (Kir1.1) and Ca2+ –activated big conductance K channel (BK). Recently, genetic studies and animal models have indicated that inwardly rectifying K channel 4.1 (Kir4.1 or Kcnj10) in distal convoluted tubule (DCT) may play a role in the regulation of K secretion in the aldosterone-sensitive distal nephron (ASDN) by targeting NaCl cotransporter (NCC). This review summarizes recent progresses regarding the role of Kir4.1 in the regulation of NCC and K secretion. Recent Findings Kir4.1 is expressed in the basolateral membrane of the DCT and plays a predominant role in contributing to the basolateral K conductance and in participating in the generation of negative membrane potential. Kir4.1 is also the substrate of src-family tyrosine kinase (SFK) and the stimulation of SFK activates Kir4.1 activity in the DCT. The genetic deletion or functional inhibition of Kir4.1 depolarizes the membrane of the DCT, inhibits ste20-proline-alanine rich kinase (SPAK) and suppresses NCC activity. Moreover, the down-regulation of Kir4.1 increases ENaC expression in the collecting duct and urinary K excretion. Finally, the mice with low Kir4.1 activity in the DCT are hypomagnesemia and hypokalemia. Summary Recent progress in exploring the regulation and the function of Kir4.1 in the DCT strongly indicates that Kir4.1plays an important role in initiating the regulation of renal K secretion by targeting NCC and it may serves as a K sensor in the kidney.

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

Cited by 47 publications

References 96 publications

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

FGF23-Klotho signaling axis in the kidney

Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity

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