FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1973609538> ?p ?o ?g. }

• W1973609538 endingPage "1375" @default.
• W1973609538 startingPage "1373" @default.
• W1973609538 abstract "This Commentary aims to integrate or interrelate the available data with the current study by Chiga and co-workers, which defines an important influence of aldosterone in the phosphorylation and thus activation of the Na+-Cl− cotransporter (NCC) in response to changes in NaCl intake and implicates the involvement of SPAK/OSR1 kinases and WNKs. This Commentary aims to integrate or interrelate the available data with the current study by Chiga and co-workers, which defines an important influence of aldosterone in the phosphorylation and thus activation of the Na+-Cl− cotransporter (NCC) in response to changes in NaCl intake and implicates the involvement of SPAK/OSR1 kinases and WNKs. An impaired ability of the kidney to excrete NaCl plays a critical pathophysiological role for a long-term increase in blood pressure. The aldosterone-sensitive distal nephron is of primary importance in the regulation of renal NaCl excretion and thus body NaCl homeostasis. The stimulatory effect of aldosterone on the epithelial sodium channel (ENaC) is well known and primarily localized to the late distal convoluted tubule (DCT) and connecting tubule. Less appreciated is the regulation of the Na+-Cl− cotransporter (NCC) in the DCT by aldosterone and other regulators. Moreover, whereas much has been learned about the molecular pathways involved in the regulation of ENaC, still relatively little is known about the determinants of NCC activity. The study by Chiga and co-workers1.Chiga M. Rai T. Yang S.-S. et al.Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.Kidney Int. 2008; 74: 1403-1409Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar (this issue) provides new in vivo evidence in this regard, as they indicate an important role of aldosterone in the regulation of NCC phosphorylation by dietary salt intake. Moreover, evidence is provided that the signaling cascade involves with-no-lysine kinase (WNK) and the mammalian STE20 (sterile 20)-like kinases SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase-1). SPAK and OSR1 were discovered through their ability to interact with, phosphorylate, and stimulate the activity of the Na+-K+-2Cl− cotransporter (NKCC1), a member of a superfamily of electroneutral cation-coupled chloride cotransporters (SLC12) (reviewed by Delpire and Gagnon2.Delpire E. Gagnon K.B. SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells.Biochem J. 2008; 409: 321-331Crossref PubMed Scopus (164) Google Scholar). The Na+-driven members of this superfamily include NKCC1 and NKCC2, as well as NCC. Fragments of these cotransporters containing a cluster of conserved threonine residues are phosphorylated in vitro by the SPAK/OSR1 kinases. The SPAK and OSR1 enzymes themselves are phosphorylated and activated by the WNK1 and WNK4 protein kinases (reviewed by Delpire and Gagnon2.Delpire E. Gagnon K.B. SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells.Biochem J. 2008; 409: 321-331Crossref PubMed Scopus (164) Google Scholar). These findings suggest that a signaling cascade including WNK1, WNK4, and SPAK/OSR1 could be involved in the regulation of the Na+-driven members of the SLC12 superfamily, including NCC. WNK1 and WNK4 are mutated in patients with pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder characterized by hyperkalemia and hypertension (reviewed by Kahle et al.3.Kahle K.T. Ring A.M. Lifton R.P. Molecular physiology of the WNK kinases.Annu Rev Physiol. 2008; 70: 329-355Crossref PubMed Scopus (189) Google Scholar). Importantly, patients with PHAII are rather sensitive to pharmacological inhibition of NCC by thiazide diuretics. Moreover, transgenic mice or gene knock-in mice carrying the PHAII mutation on the Wnk4 gene have their PHAII phenotypes corrected when treated with thiazides or when crossed with mice lacking NCC. These studies indicated that NCC is a primary effector of WNK4 mutations in the pathogenesis of PHAII. Overactivation of NCC in PHAII enhances NaCl reabsorption in the DCT and impairs the ability of the kidney to excrete NaCl and thus increases blood pressure. Enhanced NCC-mediated reabsorption of Na+ in the DCT limits the Na+ available for Na+/K+ exchange in the distal nephron, thereby impairing renal ability to excrete K+. Mutations in WNK1 and WNK4 may in addition affect other renal transport systems that can contribute to the PHAII phenotype.3.Kahle K.T. Ring A.M. Lifton R.P. Molecular physiology of the WNK kinases.Annu Rev Physiol. 2008; 70: 329-355Crossref PubMed Scopus (189) Google Scholar Importantly, the enhanced phosphorylation and activation of NCC in Wnk4 PHAII knock-in mice were associated with enhanced phosphorylation of SPAK/OSR1 kinases,4.Yang S.S. Morimoto T. Rai T. et al.Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.Cell Metab. 2007; 5: 331-344Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar implicating a potential role of WNK/SPAK/OSR1 kinases in NCC phosphorylation and activation in the PHAII phenotype. In accordance, more recent studies demonstrated that SPAK and OSR1 kinases phosphorylate human NCC at three conserved residues (Thr46, Thr55, and Thr60).5.Richardson C. Rafiqi F.H. Karlsson H.K. et al.Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.J Cell Sci. 2008; 121: 675-684Crossref PubMed Scopus (256) Google Scholar Moreover, activation of the WNK1–SPAK/OSR1 signaling pathway by treatment of HEK293 or mpkDCT-derived cells with hypotonic low-chloride conditions induced phosphorylation of NCC at the residues phosphorylated by SPAK/OSR1 kinases. Efficient phosphorylation of NCC required docking interactions between NCC and SPAK/OSR1. Finally, mutation of Thr60 in NCC markedly inhibited phosphorylation of Thr46 and Thr55, as well as NCC activation in response to hypotonic low-chloride treatment of HEK293 cells. These studies implicated the WNK1–SPAK/OSR1 signaling pathway in the phosphorylation and activation of human NCC.5.Richardson C. Rafiqi F.H. Karlsson H.K. et al.Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.J Cell Sci. 2008; 121: 675-684Crossref PubMed Scopus (256) Google Scholar+ The current study by Chiga and co-workers1.Chiga M. Rai T. Yang S.-S. et al.Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.Kidney Int. 2008; 74: 1403-1409Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar elucidated the potential physiological relevance of WNK4 and SPAK/OSR1 in the regulation of NCC by dietary salt. They showed that in wild-type mice the phosphorylation status of SPAK and OSR1, as well as of NCC (at Ser71, Thr53, and Thr58), is inversely related to NaCl intake, and immunofluorescence evidence was provided that most of the expression of phosphorylated SPAK/OSR1 was confined to the NCC-expressing nephron segments. Moreover, and intriguingly, application of aldosterone to wild-type mice on a high-salt diet increased phosphorylation of SPAK/OSR1 as well as NCC. Vice versa, blocking of aldosterone receptors by spironolactone in wild-type mice fed a low-salt diet decreased the phosphorylation status.1.Chiga M. Rai T. Yang S.-S. et al.Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.Kidney Int. 2008; 74: 1403-1409Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar Previous studies have shown that mutations of rat NCC Thr53, Thr58, and Ser71 completely reduce NCC activation in oocytes following hypotonic low-chloride treatment.6.Pacheco-Alvarez D. Cristobal P.S. Meade P. et al.The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion.J Biol Chem. 2006; 281: 28755-28763Crossref PubMed Scopus (178) Google Scholar Moreover, Thr55 and Thr60 in human NCC correspond to Thr53 and Thr58 in mouse NCC. Thus, a low-salt diet or exogenous aldosterone in mice as well as exposure of DCT-derived cells to a hypotonic low-chloride medium phosphorylates NCC at residues that correspond to the human NCC residues phosphorylated by SPAK/OSR1. Together, these studies provide very strong evidence for a role of SPAK/OSR1 in the phosphorylation and activation of NCC in response to a low-NaCl diet and aldosterone. What do we know about the regulation of WNK1 and WNK4 in the kidney and their effects on NCC? In the kidney, a 5-truncated kinase-deficient WNK1-short isoform (WNK1-S) predominates, whereas full-length WNK1-long (WNK1-L) is ubiquitously expressed at low levels. Moreover, mRNA expression of WNK1-S and WNK4 is strongest in the DCT and connecting tubule and drops sharply in the collecting duct;7.O’Reilly M. Marshall E. Macgillivray T. et al.Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo.J Am Soc Nephrol. 2006; 17: 2402-2413Crossref PubMed Scopus (107) Google Scholar that is, the expression is highest in the segments expressing NCC and the greatest activity of ENaC. WNK4 is, in addition, expressed in the thick ascending limb and the macula densa. Importantly, a high K+ intake upregulated WNK1-S and WNK4, and low intake of K+ or NaCl reduced WNK1-S in mouse kidney.7.O’Reilly M. Marshall E. Macgillivray T. et al.Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo.J Am Soc Nephrol. 2006; 17: 2402-2413Crossref PubMed Scopus (107) Google Scholar Notably, the responses to changes in K+ intake were much more pronounced than the responses to changes in NaCl intake. This stresses the importance of the system for K+ balance. It also indicates that potential secondary effects on K+ homeostasis have to be considered when effects of a given maneuver on changes in WNK expression are studied (including the responses to exogenous aldosterone or spironolactone). Expression studies in Xenopus oocytes suggested that WNK4 inhibits NCC-mediated NaCl reabsorption by reducing NCC membrane expression, and WNK1-L may in turn attenuate WNK4 (reviewed by Kahle et al.3.Kahle K.T. Ring A.M. Lifton R.P. Molecular physiology of the WNK kinases.Annu Rev Physiol. 2008; 70: 329-355Crossref PubMed Scopus (189) Google Scholar and McCormick et al.8.McCormick J.A. Yang C.L. Ellison D.H. WNK kinases and renal sodium transport in health and disease: an integrated view.Hypertension. 2008; 51: 588-596Crossref PubMed Scopus (53) Google Scholar). Kinase-deficient WNK1-S was proposed to attenuate the inhibitory influence of WNK1-L on WNK4, thereby increasing NCC expression in the membrane. WNKs are active kinases as well as scaffolds that can have unexpected effects when expressed at high levels. As a consequence, caution is needed in the interpretation of studies with overexpression. Nevertheless, the outlined findings could be integrated as follows (Figure 1): Low NaCl intake inhibits the expression of WNK1-S, thereby disinhibiting WNK1L. The latter, through effects on WNK4, stimulates NCC membrane expression, whereas WNK1-Lmediated phosphorylation of SPAK/OSR1 phosphorylates and activates NCC. Both will help to increase NCC activity and conserve NaCl. In comparison, a high-K+ diet increases WNK1-S and WNK4 expression. WNK1-S inhibits WNK1-L, thereby inhibiting the membrane expression of NCC by disinhibition of WNK4. In addition, lowering WNK1-L reduces SPAK/OSR1-mediated phosphorylation and activation of NCC. Both changes will reduce NCC activity and thus enhance the Na+ delivery for Na+/K+ exchange via ENaC, ROMK channel, and the BK channel and increase K+ excretion. Preliminary data in mice show that phosphorylation of NCC Ser71 is inversely related to dietary K+ intake (V.V. et al., unpublished observations). Both WNK1-L and WNK4 can phosphorylate SPAK/OSR1 in vitro.2.Delpire E. Gagnon K.B. SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells.Biochem J. 2008; 409: 321-331Crossref PubMed Scopus (164) Google Scholar WNK1-L-induced phosphorylation of SPAK/OSR1 and activation of NCC fits with the outlined physiological scenarios. WNK4-mediated phosphorylation and activation of SPAK/OSR1/NCC could be conflicting with the observed increase in WNK4 expression and proposed inhibition of NCC activity in response to high K+ intake (Figure 1). The current study by Chiga and co-workers1.Chiga M. Rai T. Yang S.-S. et al.Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.Kidney Int. 2008; 74: 1403-1409Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar reports that the increased phosphorylation of SPAK/OSR1/NCC in Wnk4 PHAII knock-in mice was unresponsive to changes in NaCl intake, suggesting a role of Wnk4 in the phosphorylation of SPAK/OSR1. One may speculate that the Wnk4 PHAII mutant itself phosphorylates NCC or that the mutant enhances WNK1-L activity. In addition or alternatively, the Wnk4 PHAII mutant may disinhibit WNK3, another member of the WNK family that more recently has been found to stimulate NCC activity and to interact with WNK4 and WNK1-S in vitro (reviewed by McCormick et al.8.McCormick J.A. Yang C.L. Ellison D.H. WNK kinases and renal sodium transport in health and disease: an integrated view.Hypertension. 2008; 51: 588-596Crossref PubMed Scopus (53) Google Scholar) (Figure 1). The physiological relevance of WNK3 and its role in OSR1/SPAK/NCC signaling remain to be determined. Aldosterone levels increase in response to low NaCl and high K+ intake. The opposing effects of these diets on NCC phosphorylation and activity implicate additional regulators (Figure 1). WNK4 has been reported to be phosphorylated by the serum- and glucocorticoid-regulated kinase-1 (SGK1),9.Ring A.M. Leng Q. Rinehart J. et al.An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+homeostasis.Proc Natl Acad Sci USA. 2007; 104: 4025-4029Crossref PubMed Scopus (129) Google Scholar which is expressed and activated in response to aldosterone. Notably, SGK1 phosphorylation of WNK4 alleviates the inhibitory effects of WNK4 on ENaC3.Kahle K.T. Ring A.M. Lifton R.P. Molecular physiology of the WNK kinases.Annu Rev Physiol. 2008; 70: 329-355Crossref PubMed Scopus (189) Google Scholar and possibly on NCC (Figure 1). Whether SGK1 phosphorylation of WNK4 affects phosphorylation of OSR1/SPAK/NCC or the membrane expression of NCC remains to be determined. Mice lacking Sgk1 have an impaired renal ability to conserve NaCl and excrete K+.10.Vallon V. Wulff P. Huang D.Y. et al.Role of Sgk1 in salt and potassium homeostasis.Am J Physiol Regul Integr Comp Physiol. 2005; 288: R4-R10Crossref PubMed Scopus (64) Google Scholar Preliminary data indicate that phosphorylation of NCC Ser71 in response to a low-NaCl diet is attenuated in mice lacking Sgk1; in comparison, a high-K+ diet induced hyperkalemia in these mice, associated with an exaggerated suppression of NCC Ser71 phosphorylation, which may serve to deliver more Na+ to the distal segments of impaired Na+/K+ exchange in the absence of Sgk1 (V.V. et al., unpublished observations). In summary, NCC in the distal convoluted tubule plays a critical role in NaCl and, indirectly, in K+ homeostasis. Recent studies implicated its regulation by WNK kinases. The current in vivo study by Chiga and co-workers1.Chiga M. Rai T. Yang S.-S. et al.Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.Kidney Int. 2008; 74: 1403-1409Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar has defined an important influence of aldosterone in the phosphorylation and activation of NCC in response to changes in NaCl intake, and implicates the involvement of SPAK/OSR1 kinases and WNKs. The author declared no competing interests. This work was supported with funds provided by the National Institutes of Health (DK56248, DK28602, GM66232), the American Heart Association (0655232Y), and the Research Service of the Department of Veterans Affairs." @default.
• W1973609538 created "2016-06-24" @default.
• W1973609538 creator A5085734264 @default.
• W1973609538 date "2008-12-01" @default.
• W1973609538 modified "2023-10-18" @default.
• W1973609538 title "Regulation of the Na+-Cl− cotransporter by dietary NaCl: a role for WNKs, SPAK, OSR1, and aldosterone" @default.
• W1973609538 cites W1965407415 @default.
• W1973609538 cites W2007555006 @default.
• W1973609538 cites W2015998887 @default.
• W1973609538 cites W2058574926 @default.
• W1973609538 cites W2088572009 @default.
• W1973609538 cites W2125093965 @default.
• W1973609538 cites W2141617464 @default.
• W1973609538 cites W2153784583 @default.
• W1973609538 cites W2154100497 @default.
• W1973609538 cites W2155147896 @default.
• W1973609538 doi "https://doi.org/10.1038/ki.2008.477" @default.
• W1973609538 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2944250" @default.
• W1973609538 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19008908" @default.
• W1973609538 hasPublicationYear "2008" @default.
• W1973609538 type Work @default.
• W1973609538 sameAs 1973609538 @default.
• W1973609538 citedByCount "10" @default.
• W1973609538 countsByYear W19736095382013 @default.
• W1973609538 countsByYear W19736095382014 @default.
• W1973609538 countsByYear W19736095382015 @default.
• W1973609538 countsByYear W19736095382016 @default.
• W1973609538 countsByYear W19736095382018 @default.
• W1973609538 countsByYear W19736095382020 @default.
• W1973609538 crossrefType "journal-article" @default.
• W1973609538 hasAuthorship W1973609538A5085734264 @default.
• W1973609538 hasBestOaLocation W19736095381 @default.
• W1973609538 hasConcept C104317684 @default.
• W1973609538 hasConcept C120405084 @default.
• W1973609538 hasConcept C126322002 @default.
• W1973609538 hasConcept C134018914 @default.
• W1973609538 hasConcept C149011108 @default.
• W1973609538 hasConcept C178790620 @default.
• W1973609538 hasConcept C185592680 @default.
• W1973609538 hasConcept C188053792 @default.
• W1973609538 hasConcept C2778525890 @default.
• W1973609538 hasConcept C537181965 @default.
• W1973609538 hasConcept C55493867 @default.
• W1973609538 hasConcept C6507245 @default.
• W1973609538 hasConcept C71924100 @default.
• W1973609538 hasConceptScore W1973609538C104317684 @default.
• W1973609538 hasConceptScore W1973609538C120405084 @default.
• W1973609538 hasConceptScore W1973609538C126322002 @default.
• W1973609538 hasConceptScore W1973609538C134018914 @default.
• W1973609538 hasConceptScore W1973609538C149011108 @default.
• W1973609538 hasConceptScore W1973609538C178790620 @default.
• W1973609538 hasConceptScore W1973609538C185592680 @default.
• W1973609538 hasConceptScore W1973609538C188053792 @default.
• W1973609538 hasConceptScore W1973609538C2778525890 @default.
• W1973609538 hasConceptScore W1973609538C537181965 @default.
• W1973609538 hasConceptScore W1973609538C55493867 @default.
• W1973609538 hasConceptScore W1973609538C6507245 @default.
• W1973609538 hasConceptScore W1973609538C71924100 @default.
• W1973609538 hasIssue "11" @default.
• W1973609538 hasLocation W19736095381 @default.
• W1973609538 hasLocation W19736095382 @default.
• W1973609538 hasLocation W19736095383 @default.
• W1973609538 hasLocation W19736095384 @default.
• W1973609538 hasOpenAccess W1973609538 @default.
• W1973609538 hasPrimaryLocation W19736095381 @default.
• W1973609538 hasRelatedWork W1982498018 @default.
• W1973609538 hasRelatedWork W1993396385 @default.
• W1973609538 hasRelatedWork W2013015015 @default.
• W1973609538 hasRelatedWork W2132758671 @default.
• W1973609538 hasRelatedWork W2138029694 @default.
• W1973609538 hasRelatedWork W2155976167 @default.
• W1973609538 hasRelatedWork W2342803240 @default.
• W1973609538 hasRelatedWork W2748952813 @default.
• W1973609538 hasRelatedWork W2758566500 @default.
• W1973609538 hasRelatedWork W4312052120 @default.
• W1973609538 hasVolume "74" @default.
• W1973609538 isParatext "false" @default.
• W1973609538 isRetracted "false" @default.
• W1973609538 magId "1973609538" @default.
• W1973609538 workType "article" @default.