The Thiazide-sensitive Na+-Cl- Cotransporter: Molecular Biology, Functional Properties, and Regulation by WNKs

Overview

Journal Am J Physiol Renal Physiol

Publisher American Physiological Society

Specialties Nephrology
Physiology

Date 2009 May 29

PMID 19474192

Citations 49

Authors

Gerardo Gamba

Affiliations

Soon will be listed here.

Abstract

The thiazide-sensitive Na+-Cl(-) cotransporter is the major salt reabsorption pathway in the distal convoluted tubule, which is located just after the macula densa at the beginning of the aldosterone-sensitive nephron. This cotransporter was identified at the molecular level in the early 1990s by the pioneering work of Steven C. Hebert and coworkers, opening the molecular area, not only for the Na+-Cl(-) cotransporter but also for the family of electroneutral cation-coupled chloride cotransporters that includes the loop diuretic-sensitive Na+-K+-2Cl(-) cotransporter of the thick ascending limb of Henle's loop. This work honoring the memory of Steve Hebert presents a brief review of our current knowledge about salt and water homeostasis generated as a consequence of cloning the cotransporter, with particular emphasis on the molecular biology, physiological properties, human disease due to decreased or increased activity of the cotransporter, and regulation of the cotransporter by a family of serine/threonine kinases known as WNK. Thus one of the legacies of Steve Hebert is a better understanding of salt and water homeostasis.

Citing Articles

Hypoxia Modulates Sodium Chloride Co-transporter via CaMKII-β Pathway: An In Vitro Study with mDCT15 Cells.

Liang L, Ueda K, Ogura S, Shimosawa T Life (Basel). 2024; 14(10).

PMID: 39459529 PMC: 11508333. DOI: 10.3390/life14101229.

Pathophysiological role of Na-Cl cotransporter in kidneys, blood pressure, and metabolism.

You R, Jia Z Hum Cell. 2024; 37(5):1306-1315.

PMID: 38985392 DOI: 10.1007/s13577-024-01099-2.

Role of calcineurin in regulating renal potassium (K) excretion: Mechanisms of calcineurin inhibitor-induced hyperkalemia.

Duan X, Zhang C, Wang W, Lin D Acta Physiol (Oxf). 2024; 240(8):e14189.

PMID: 38860527 PMC: 11250626. DOI: 10.1111/apha.14189.

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

Sun J, Zhang C, Su X, Zhou H, Zhou S, Jiang M J Orthop Surg Res. 2024; 19(1):147.

PMID: 38373964 PMC: 10875773. DOI: 10.1186/s13018-024-04627-w.

Navigating the multifaceted intricacies of the Na-Cl cotransporter, a highly regulated key effector in the control of hydromineral homeostasis.

Rioux A, Nsimba-Batomene T, Slimani S, Bergeron N, Gravel M, Schreiber S Physiol Rev. 2024; 104(3):1147-1204.

PMID: 38329422 PMC: 11381001. DOI: 10.1152/physrev.00027.2023.

References

Vazquez N, Monroy A, Dorantes E, Munoz-Clares R, Gamba G . Functional differences between flounder and rat thiazide-sensitive Na-Cl cotransporter. Am J Physiol Renal Physiol. 2002; 282(4):F599-607. DOI: 10.1152/ajprenal.00284.2001. View

Xu B, Stippec S, Chu P, Lazrak A, Li X, Lee B . WNK1 activates SGK1 to regulate the epithelial sodium channel. Proc Natl Acad Sci U S A. 2005; 102(29):10315-20. PMC: 1177404. DOI: 10.1073/pnas.0504422102. View

Wilson F, Kahle K, Sabath E, Lalioti M, Rapson A, Hoover R . Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A. 2003; 100(2):680-4. PMC: 141056. DOI: 10.1073/pnas.242735399. View

OReilly M, Marshall E, Speirs H, Brown R . WNK1, a gene within a novel blood pressure control pathway, tissue-specifically generates radically different isoforms with and without a kinase domain. J Am Soc Nephrol. 2003; 14(10):2447-56. DOI: 10.1097/01.asn.0000089830.97681.3b. View

San-Cristobal P, Ponce-Coria J, Vazquez N, Bobadilla N, Gamba G . WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter. Am J Physiol Renal Physiol. 2008; 295(4):F1199-206. PMC: 2576145. DOI: 10.1152/ajprenal.90396.2008. View

Yang C, Zhu X, Ellison D . The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest. 2007; 117(11):3403-11. PMC: 2045602. DOI: 10.1172/JCI32033. View

Delpire E, Rauchman M, Beier D, Hebert S, Gullans S . Molecular cloning and chromosome localization of a putative basolateral Na(+)-K(+)-2Cl- cotransporter from mouse inner medullary collecting duct (mIMCD-3) cells. J Biol Chem. 1994; 269(41):25677-83. View

Wei Y, Zavilowitz B, Satlin L, Wang W . Angiotensin II inhibits the ROMK-like small conductance K channel in renal cortical collecting duct during dietary potassium restriction. J Biol Chem. 2006; 282(9):6455-62. PMC: 2822470. DOI: 10.1074/jbc.M607477200. View

Gamba G . WNK lies upstream of kinases involved in regulation of ion transporters. Biochem J. 2005; 391(Pt 1):e1-3. PMC: 1237149. DOI: 10.1042/BJ20051345. View

10.

de Jong J, Willems P, Mooren F, van den Heuvel L, Knoers N, Bindels R . The structural unit of the thiazide-sensitive NaCl cotransporter is a homodimer. J Biol Chem. 2003; 278(27):24302-7. DOI: 10.1074/jbc.M303101200. View

11.

Abuladze N, Yanagawa N, Lee I, Jo O, Newman D, Hwang J . Peripheral blood mononuclear cells express mutated NCCT mRNA in Gitelman's syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport. J Am Soc Nephrol. 1998; 9(5):819-26. DOI: 10.1681/ASN.V95819. View

12.

Hebert S, Mount D, Gamba G . Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Arch. 2003; 447(5):580-93. DOI: 10.1007/s00424-003-1066-3. View

13.

Velazquez H, Silva T, Andujar E, Reilly R, Desir G, Ellison D . Rabbit distal convoluted tubule coexpresses NaCl cotransporter and 11 beta-hydroxysteroid dehydrogenase II mRNA. Kidney Int. 1998; 54(2):464-72. DOI: 10.1046/j.1523-1755.1998.00036.x. View

14.

Mercado A, Vazquez N, Song L, Cortes R, Enck A, Welch R . NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter. Am J Physiol Renal Physiol. 2005; 289(6):F1246-61. DOI: 10.1152/ajprenal.00464.2004. View

15.

Yoo D, Kim B, Campo C, Nance L, King A, Maouyo D . Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A. J Biol Chem. 2003; 278(25):23066-75. DOI: 10.1074/jbc.M212301200. View

16.

Moreno E, Cristobal P, Rivera M, Vazquez N, Bobadilla N, Gamba G . Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding. J Biol Chem. 2006; 281(25):17266-17275. DOI: 10.1074/jbc.M602614200. View

17.

Drewnowska K, Baumgarten C . Regulation of cellular volume in rabbit ventricular myocytes: bumetanide, chlorothiazide, and ouabain. Am J Physiol. 1991; 260(1 Pt 1):C122-31. DOI: 10.1152/ajpcell.1991.260.1.C122. View

18.

Gordon R . Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension. 1986; 8(2):93-102. DOI: 10.1161/01.hyp.8.2.93. View

19.

Dvorak M, De Joussineau C, Carter D, Pisitkun T, Knepper M, Gamba G . Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone. J Am Soc Nephrol. 2007; 18(9):2509-16. PMC: 2216427. DOI: 10.1681/ASN.2007030348. View

20.

San-Cristobal P, de Los Heros P, Ponce-Coria J, Moreno E, Gamba G . WNK kinases, renal ion transport and hypertension. Am J Nephrol. 2008; 28(5):860-70. PMC: 2820349. DOI: 10.1159/000139639. View