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Review Article | Open Access

NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension

Sergei N. Orlova,b,( ), Svetlana V. Koltsovaa, Leonid V. Kapilevichb,c, Svetlana V. Gusakovac, Nickolai O. Dulind
Faculty of Biology, M.V. Lomonosov Moscow State University, Russia
Тomsk State University, Russia
Siberian State Medical University, Russia
University of Chicago Department of Medicine, USA

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

This review summarizes the data on the functional significance of ubiquitous (NKCC1) and renal-specific (NKCC2) isoforms of electroneutral sodium, potassium and chloride cotransporters. These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid, respectively. Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume. However, the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds.

Keywords

HypertensionSmooth muscleIntracellular chlorideMyogenic toneNeuronal cellNKCC cotransport

References

1

Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005;85:423-493.
Crossref Google Scholar
2

Orlov SN, Mongin AA. Salt sensing mechanisms in blood pressure regulation and hypertension. Am J Physiol Heart Circ Physiol. 2007;293:H2039-H2053.
Crossref Google Scholar
3

Markadieu N, Delpire E. Physiology and pathophysiology of SLC12A1/2 transporters. Pfluger Arch - Eur J Physiol. 2014;466:91-105.
Crossref Google Scholar
4

Lang F, Busch G, Ritter M, et al. Functional significance of cell volume regulatory mechanisms. Physiol Rev. 1998;78:247-306.
Crossref Google Scholar
5

Mongin AA, Orlov SN. Mechanisms of cell volume regulation and possible nature of the cell volume sensor. Pathophysiology. 2001;8:77-88.
Crossref Google Scholar
6

Orlov SN, Pokudin NI, Kotelevtsev YuV, Gulak PV. Volume-dependent regulation of ion transport and membrane phosphorylation in human and rat erythrocytes. J Membr Biol. 1989;107:105-117.
Crossref Google Scholar
7

Adragna N, Di Fulvio M, Lauf PK. Regulation of K-Cl cotransport: from function to genes. J Membr Biol. 2004;201:109-137.
Crossref Google Scholar
8

Orlov SN. Ion transport across erythrocyte membrane: mechanisms and volume-dependent regulation. Sov Sci Rev F Physiol Gen Biol. 1994;8:1-48.
Google Scholar
9

Orlov SN, Tremblay J, Hamet P. Cell volume in vascular smooth muscle is regulated by bumetanide-sensitive ion transport. Am J Physiol. 1996;270:C1388-C1397.
Crossref Google Scholar
10

Hoffmann EK, Lambert IH, Pedersen SF. Physiology of cell volume regulation in vertebrates. Physiol Rev. 2009;89:193-277.
Crossref Google Scholar
11

Orlov SN, Platonova AA, Hamet P, Grygorczyk R. Cell volume and monovalent ion transporters: their role in the triggereing and progression of the cell death machinery. Am J Physiol Cell Physiol. 2013;305:C361-C372.
Crossref Google Scholar
12
Alvarez-Leefmans FJ. Intracellular chloride regulation. In: Sperelakis N, ed. Cell Physiology Source Book. A Molecular Approach. San Diego, CA: Academic; 2001:301-318.
Crossref
13

Chipperfield AR, Harper AA. Chloride in smooth muscle. Prog Biophys Mol Biol. 2001;74:175-221.
Crossref Google Scholar
14

Davis JPL, Chipperfield AR, Harper AA. Accumulation of intracellular chloride by (Na-K-Cl) cotransport in rat arterial smooth muscle is enhanced in deoxycorticosterone acetate (DOCA)/salt hypertension. J Mol Cell Cardiol. 1993;25:233-237.
Crossref Google Scholar
15

Anfinogenova YJ, Baskakov MB, Kovalev IV, Kilin AA, Dulin NO, Orlov SN. Cell-volume-dependent vascular smooth muscle contraction: role of Na+,K+,2Cl- cotransport, intracellular Cl- and L-type Ca2+ channels. Pflьgers Arch. 2004;449:42-55.
Crossref Google Scholar
16

Barthelmebs M, Stephan D, Fontaine C, Grima M, Imbs JL. Vascular effects of loop diuretics: an in vivo and in vitro study in the rat. Schmiedeb Arch Pharmacol. 1994;349:209-216.
Crossref Google Scholar
17

Lavallee SL, Iwamoto LM, Claybaugh JR, Dressel MV, Sato AK, Nakamura KT. Furosemide-induced airway relaxation in guinea pigs: relation to Na-K-2Cl cotransporet function. Am J Physiol. 1997;273:L211-L216.
Crossref Google Scholar
18

Tian R, Aalkjaer C, Andreasen F. Mechanisms behind the relaxing effect of furosemide on the isolated rabbit ear artery. Pharmacol Toxicol. 1990;67:406-410.
Crossref Google Scholar
19

Kovalev IV, Baskakov MB, Anfinogenova YJ, et al. Effect of Na+,K+,2Cl- cotransport inhibitor bumetanide on electrical and contractile activity of smooth muscle cells in guinea pig ureter. Bull Exp Biol Med. 2003;136:145-149.
Crossref Google Scholar
20

Kovalev IV, Baskakov MB, Medvedev MA, et al. Na+,K+,2Cl- cotransport and chloride permeability of the cell membrane in mezaton and histamine regulation of electrical and contractile activity in smooth muscle cells from the guinea pig ureter. Russ Physiol J. 2008;93:306-317.
Google Scholar
21

Stanke F, Devillier P, Breant D, et al. Furosemide inhibits angiotensin II-induced contraction on human vascular smooth muscle. Br J Clin Pharmacol. 1998;46:571-575.
Crossref Google Scholar
22

Stanke-Labesque F, Craciwski JL, Bedouch P, et al. Furosemide inhibits thrombaxane A2-induced contraction in isolated human internal artery and saphenous vein. J Cardiovasc Pharmacol. 2000;35:531-537.
Crossref Google Scholar
23

Wang X, Breaks J, Loutzenhiser K, Loutzenhiser R. Effects of inhibition of the Na+/K+/2Cl- cotransporter on myogenic and angiotensin II responses of the rat afferent arteriole. Am J Physiol Ren Physiol. 2007;292:F999-F1006.
Crossref Google Scholar
24

Mozhayeva MG, Bagrov YY. The inhibitory effects of furosemide on Ca2+ influx pathways associated with oxytocin-induced contractions of rat myometrium. Gen Physiol Biophys. 1995;14:427-436.
Google Scholar
25

Mozhayeva MG, Bagrov YY, Ostretsova IB, Gillespie JI. The effect of furosemide on oxytocin-induced contractions of the rat myometrium. Exp Physiol. 1994;79:661-667.
Crossref Google Scholar
26

Akar F, Skinner E, Klein JD, Jena M, Paul RJ, O'Neill WC. Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl- cotransporter in rat aorta. Am J Physiol. 1999;276:C1383-C1390.
Crossref Google Scholar
27

Garg P, Martin C, Elms SC, et al. Effect of the Na-K-2Cl cotransporter NKCC1 on systematic blood pressure and smooth muscle tone. Am J Physiol Heart Circ Physiol. 2007;292:H2100-H2105.
Crossref Google Scholar
28

Palacios J, Espinoza F, Munita C, Cifuentes F, Michea L. Na+-K+-2Cl- cotransporter is implicated in gender differences in the response of the rat aorta to phenylephrine. Br J Pharmacol. 2006;148:964-972.
Crossref Google Scholar
29

Koltsova SV, Maximov GV, Kotelevtsev SV, et al. Myogenic tome in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+,K+,2Cl- cotransport-dependent signaling. Purinergic Signal. 2009;5:343-349.
Crossref Google Scholar
30

Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiol Rev. 1999;79:387-423.
Crossref Google Scholar
31

Hill MA, Davis MJ, Meininger GA, Potocnik SJ, Murphy TV. Arteriolar myogenic signaling mechanisms: implications for local vascular functions. Clin Hemorheol Microcirc. 2006;34:67-79.
Google Scholar
32

Schubert R, Mulvany MJ. The myogenic response: established facts and attractive hypothesis. Clin Sci. 1999;96:313-326.
Crossref Google Scholar
33

Koltsova SV, Kotelevtsev SV, Tremblay J, Hamet P, Orlov SN. Excitation-contraction coupling in resistant mesenteric arteries: evidence for NKCC1-mediated pathway. Biochem Biophys Res Commun. 2009;379:1080-1083.
Crossref Google Scholar
34

Delpire E, Austin TM. Kinase regulation of Na+-K+-2Cl- cotransport in primary neurons. J Physiol. 2010;588:3365-3373.
Crossref Google Scholar
35

Kahle KT, Staley KJ, Nahed BV, et al. Roles of the cation-chloride cotransporters in neurological disease. Nat Clin Pract Neurol. 2008;4:490-503.
Crossref Google Scholar
36

Loscher W, Puskarjov M, Kaila K. Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology. 2013;69:62-74.
Crossref Google Scholar
37

Wright FS, Schnermann J. Interference with feedback control of glomerular filtration rate by furosemide, triflocin, and cyanide. J Clin Invest. 1974;53:1695-1708.
Crossref Google Scholar
38

Simon DB, Karet FE, Hamdan JM, Di Pietro A, Sanjad SA, Lifton RP. Bartter's syndrome, hypokalemic alkalosis with hypercalciuria, is caused by mutation of Na-K-2Cl cotransporter NKCC2. Nat Genet. 1996;13:183-188.
Crossref Google Scholar
39
Briggs JP, Schnermann J. Control of renin release and glomerular vascular tone by the juxtaglomerular apparatus. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. New York: Raven Press Ltd.; 1995:1359-1384.
40

Schermann J, Briggs JP. Tubuloglomerular feedback: mechanistic insights from gene-manipulated mice. Kidney Int. 2008;74:418-426.
Crossref Google Scholar
41

Singh P, Thomson SC. Renal homeostasis and tubuloglomerular feedback. Curr Opin Nephrol Hypert. 2010;19:59-64.
Crossref Google Scholar
42

Knepper MA, Inoue T. Regulation of aquaporin-2 water channel trafficking by vasopressin. Curr Opin Cell Biol. 1997;9:560-564.
Crossref Google Scholar
43

Borgnia M, Nielsen S, Engel A, Agre P. Cellular and molecular biology of the aquaporin water channels. Annu Rev Biochem. 1999;68:425-458.
Crossref Google Scholar
44

Bell PD, Lapointe J-Y, Peti-Peterdi J. Macula densa cell signaling. Annu Rev Physiol. 2003;65:481-500.
Crossref Google Scholar
45

Laamarti MA, Bell PD, Lapointe J-Y. Transport and regulatory properties of the apical Na-K-2Cl cotransporter of macula densa cells. Am J Physiol. 1998;275:F703-F709.
Crossref Google Scholar
46

Nielsen S, Maunsbach AB, Ecelbarger CA, Knepper MA. Ultrasructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney. Am J Physiol. 1998;275:F885-F893.
Crossref Google Scholar
47

Nashat FS, Tappin JW, Wilcox CS. The renal blood flow and the glomerylar filtration rate of anaesthetized dogs during acute changes in plasma sodium concentration. J Physiol. 1976;256:731-745.
Crossref Google Scholar
48

Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71:726-735.
Crossref Google Scholar
49

Briggs JP, Schermann J, Wright FS. Failure of tubule fluid osmolarity to affect feedback regulation of glomerular filtration. Am J Physiol. 1980;239:F427-F432.
Crossref Google Scholar
50

Schnermann J, Briggs J, Wright FS. Feedback-mediated reduction of glomerular filtration rate during infusion of hypertonic saline. Kidney Int. 1981;20:462-468.
Crossref Google Scholar
51

Schnermann J, Ploth DW, Hermle M. Activation of tubulo-glomerular feedback by chloride transport. Pflugers Arch. 1976;362:229-240.
Crossref Google Scholar
52

Russell JM. Sodium-potassium-chloride cotransport. Physiol Rev. 2000;80:212-276.
Crossref Google Scholar
53

Payne JA, Forbush B. Alternatively spliced isoforms of the putative renal Na-K-Cl cotransporter are differently distributed within the rabbit kidney. Proc Natl Acad Sci U. S. A. 1994;91:4544-4548.
Crossref Google Scholar
54

Igarashi P, Vandel Heuvel GB, Payne JA, Forbush BI. Cloning, embryonic expression, and alternative splicing of a murine kidney-specific Na-K-Cl cotransporter. Am J Physiol. 1995;269:F405-F418.
Crossref Google Scholar
55

Castrop H, Schnermann J. Isofroms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance. Am J Physiol Ren Physiol. 2008;295:F859-F866.
Crossref Google Scholar
56

Yang T, Huang YC, Singh I, Schnermann J, Briggs JP. Localization of bumetanide- and thiazide-sensitive Na-K-Cl cotransporters along the rat nephron. Am J Physiol. 1998;271:F931-F939.
Crossref Google Scholar
57

Brunet GM, Gagnon E, Simard CF, et al. Novel insights regarding the operational characteristics and theological purpose of the renal Na+-K+-Cl- cotransporter (NKCC2s) splice variants. J Gen Physiol. 2005;126:325-337.
Crossref Google Scholar
58

Plata C, Meade P, Vazquez N, Hebert SC, Gamba G. Functional properties of the apical Na+,K+,2Cl- cotransporter isoforms. J Biol Chem. 2002;277:11004-11012.
Crossref Google Scholar
59

Gimenez I, Isenring P, Forbush BI. Spatially distributed alternatively spliced variants of the renal Na-K-Cl cotransporter exhibit dramatically different affinities for the transported ions. J Biol Chem. 2002;277:8767-8770.
Crossref Google Scholar
60

Lu L, Fraser JA. Functional consequences of NKCC2 splice isoforms: insight from a Xenopus oocyte model. Am J Physiol Ren Physiol. 2014;306:F710-F720.
Crossref Google Scholar
61

Oppermann M, Mizel D, Huang G, et al. Macula densa control of renin secretion and proglomerular resistance in mice with selective deletion of the B isoform of Na, K,2Cl co-transporter. J Am Soc Nephrol. 2006;17:2143-2152.
Crossref Google Scholar
62

Oppermann M, Mizel D, Kim SM, et al. Renal function in mice with targeted disruption of the A isoform of the Na-K-2Cl- co-transporter. J Am Soc Nephrol. 2007;18:440-448.
Crossref Google Scholar
63

Lorenz JN, Kotchen TA, Ott CE. Effect of Na and Cl infusion on loop function and plasma renin activity. Am J Physiol. 1990;258:F1328-F1335.
Crossref Google Scholar
64

Peti-Peterdi J, Bebok Z, Lapointe J-Y, Bell PD. Cytosolic [Na] regulation in macula densa cells: novel role for an apical H: K-ATPase. Am J Physiol Ren Physiol. 2002;282:F329.
Crossref Google Scholar
65

O'Grady SM, Palfrey HC, Field M. Characteristics and functions of Na-K-Cl cotransport in epithelial tissues. Am J Physiol. 1987;253:C177-C192.
Crossref Google Scholar
66

Tuck ML, Gross C, Maxwell MH, Brickman AS, Krasnoshtein G, Mayes D. Erythrocyte Na+,K+ cotransport and Na+,K+ pump in black and caucasian hypertensive patients. Hypertension. 1984;6:536-544.
Crossref Google Scholar
67

Weder AB, Torretti BA, Julius S. Racial differences in erythrocyte cation transport. Hypertension. 1984;6:115-123.
Crossref Google Scholar
68

Canessa M. The Na-K-Cl cotransport in essential hypertension: cellular functions and genetic environment interactions. Int J Cardiol. 1989;25:S37-S45.
Crossref Google Scholar
69

Orlov SN, Pausova Z, Gossard F, et al. Na+,K+,Cl- cotransport is decreased in African American vs French-Canadian hypertensives: lack of impact of gender and plasma lipids (Abstract). J Hypertens. 2001;19(suppl. 2):S46.
Google Scholar
70

Orlov SN, Gossard F, Pausova Z, et al. Decreased NKCC1 activity in erythrocytes from African-Americans with hypertension and dyslipidemia. Am J Hypertens. 2010;23:321-326.
Crossref Google Scholar
71

Orlov SN. Decreased Na+,K+,Cl- cotransport and salt retention in Blacks: a provocative hypothesis. J Hypertens. 2005;23:1929-1930.
Crossref Google Scholar
72

Flagella M, Clarke LL, Miller ML, et al. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem. 1999;274:26946-26955.
Crossref Google Scholar
73

Saito T, Hartell NA, Muguruma H, Hotta S, Sasaki S, Ito M. Light dose and time dependency of photodynamic cell membrane damage. Photochem Photobiol. 1998;68:745-748.
Crossref Google Scholar
74

Dill DB, Yousef MK, Goldman A, Hillyard SD, Davis TP. Volume and composition of hand sweat of white and black men and women in desert walk. Am J Antropol. 1983;61:67-73.
Crossref Google Scholar
75

Giebisch G. Renal potassium transport: mechanisms and regulation. Am J Physiol. 1998;274:F817-F833.
Crossref Google Scholar
76

Andrew PM, Jones DW, Wofford MR, et al. Ethnicity and unprovoked hypokalemia in the atherosclerosis risk in communities study. Am J Hypertens. 2002;15:594-599.
Crossref Google Scholar
77

Sato K, Kang WH, Saga K, Sato KT. Bilogy of sweet glands and their disorders. I. Normal sweat gland function. J Am Acad Dermatol. 1989;20:537-563.
Crossref Google Scholar
78

O'Shaughnessy KM, Karet FE. Salt handling in hypertension. Annu Rev Nutr. 2006;26:343-365.
Crossref Google Scholar
79
Guyton AC. Arterial Pressure and Hypertension. Philadelphia: WB Saunders Co; 1980.
80

Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545-556.
Crossref Google Scholar
81

Lifton RP. Genetic dissection of human blood pressure variation: common pathways from rare phenotypes. Harvey Lect. 2005;100:71-101.
Google Scholar
82

Guyton AC. Blood pressure control – special role of the kidney and body fluids. Science. 1991;252:1813-1816.
Crossref Google Scholar
83

Simon DB, Nelson-Williams C, Bia J, et al. Gitelman's varaint of Bartter's syndrome, inhereted hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996;12:24-30.
Crossref Google Scholar
84

Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001;293:1107-1112.
Crossref Google Scholar
85

Hamet P, Pausova Z, Adarichev V, Adaricheva K, Tremblay J. Hypertension: genes and environment. J Hypertens. 1998;16:397-418.
Crossref Google Scholar
86
Pickering GW. Systematic arterial pressure. In: Fishman AP, Richards DW, eds. Circulation of the Blood. Men and Ideas. 1964:487-541. London.
87

Schiebl IM, Rosenauer A, Kattler V, Minuth WW, Oppermann M, Castrop H. Dietary salt intake modulates differential splicong of the Na-K-2Cl cotransporter NKCC2. Am J Physiol Ren Physiol. 2013;305:F1139-F1148.
Crossref Google Scholar
88

Orlov SN, Hamet P. Salt and gene expression: evidence for Na+i,K+i-mediated signaling pathways. Pflugers Arch. 2015;467(3):489-498.
Crossref Google Scholar
89

Davies M, Fraser SA, Galic S, et al. Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK. Am J Physiol Ren Physiol. 2014;307:F96-F106.
Crossref Google Scholar
90

Jones AW. Altered ion transport in vascular smooth muscle from spontaneously hypertensive rats. Influence of aldosterone, norepinephrine and angiotensin. Circ Res. 1973;33:563-572.
Crossref Google Scholar
91

Postnov YuV, Orlov SN, Gulak PV, Shevchenko AS. Altered permeability of the erythrocyte membrane for sodium and potassium in spontaneously hypertensive rats. Pflugers Arch. 1976;365:257-263.
Crossref Google Scholar
92

Postnov YuV, Orlov SN, Shevchenko AS, Adler AM. Altered sodium permeability, calcium binding and Na-K-ATPase activity in the red blood cell membrane in essential hypertension. Pflugers Arch. 1977;371:263-269.
Crossref Google Scholar
93

Postnov YuV, Orlov SN. Ion transport across plasma membrane in primary hypertension. Physiol Rev. 1985;65:904-945.
Crossref Google Scholar
94

Orlov SN, Adragna N, Adarichev VA, Hamet P. Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension. Am J Physiol. 1999;276:C511-C536.
Crossref Google Scholar
95

Garay RP, Alda O. What can we learn from erythrocyte Na-K-Cl cotransporter NKCC1 in human hypertension. Pathophysiology. 2007;14:167-170.
Crossref Google Scholar
96

Orlov SN, Tremblay J, Hamet P. NKCC1 and hypertension: a novel therapeutic target involved in regulation of vascular tone and renal function. Curr Opin Nephrol Hypert. 2010;19:163-168.
Crossref Google Scholar
97

Orlov SN, Koltsova SV, Tremblay J, Baskakov MB, Hamet P. NKCC1 and hypertension: role in the regulation of vascular smooth muscle contractions and myogenic tone. Ann Med. 2012;44:S111-S118.
Crossref Google Scholar
98

Bianchi G, Ferrari P, Trizio P, et al. Red blood cell abnormalities and spontaneous hypertension in rats. A genetically determined link. Hypertension. 1985;7:319-325.
Crossref Google Scholar
99

Kotelevtsev YuV, Orlov SN, Pokudin NI, Agnaev VM, Postnov YuV. Genetic analysis of inheritance of Na+,K+ cotransport, calcium level in erythrocytes and blood pressure in F2 hybrids of spontaneously hypertensive and normotensive rats. Bull Exp Biol Med. 1987;103:456-458.
Crossref Google Scholar
100

Meyer JW, Flagella M, Sutliff RL, et al. Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na+-K+-2Cl- cotransporter. Am J Physiol. 2002;283:H1846-H1855.
Crossref Google Scholar
101

Wall SM, Knepper MA, Hassel KA, et al. Hypotension in NKCC1 null mice: role of the kidney. Am J Physiol Ren Physiol. 2006;290:F409-F416.
Crossref Google Scholar
102

Lee H-A, Baek I, Seok YM, et al. Promoter hypomethylation upregulates Na+-K+-2Cl- cotransporyter 1 in spontaneously hypertensive rats. Biochem Biophys Res Commun. 2010;396:252-257.
Crossref Google Scholar
103

Cho H-M, Lee H-A, Kim HY, Han HS, Kim IK. Expression of Na+,K+-2Cl- cotransporter is epigenetically regulated during postnatal development of hypertension. Am J Hypertens. 2011;12:1286-1293.
Crossref Google Scholar
104

Mancia G, Grassi G, Giannattasio C, Seravalle G. Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension. 1999;34:724-728.
Crossref Google Scholar
105

Schlaich MP, Lambert E, Kaye DM, et al. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension. 2004;43:169-175.
Crossref Google Scholar
106

Huang BS, Amin MS, Leenen FHH. The central role of the brain in salt-sensitive hypertension. Curr Opin Cardiol. 2006;21:295-394.
Crossref Google Scholar
107

Leenen FHH. The central role of the brain aldosterone-“ouabain” pathway in salt-sensitive hypertension. Biochim Biophys Acta. 2010;1802:1132-1139.
Crossref Google Scholar
108

Judy WV, Watanabe AM, Henry PD, Besch HR, Murphy WR, Hockel GM. Sympathetic nerve activity: role in regulation of blood pressure in the spontaneously hypertensive rats. Circ Res. 1976;38:21-29.
Crossref Google Scholar
109

Allen AM. Inhibition of the hypothalamic paraventricular nucleus in spontaneousl hypertensive rats dramatically reduces sympathetic vasomotor tone. Hypertension. 2002;39:275-280.
Crossref Google Scholar
110

Li DP, Pan HL. Glutamatergic inputs in the hypothalamic paraventricular nucleus maintain sympathetic vasomotor tone in hypertension. Hypertension. 2007;49:916-925.
Crossref Google Scholar
111

Pyner S, Coote JH. Identification of branching paraventricular neurins of the hypothalamus that project to the rostroventrolateral medulla and spinal cord. Neuroscience. 2000;100:549-556.
Crossref Google Scholar
112

Li DP, Pan HL. Role of GABAA and GABAB receptors in paraventricular nucelus in control sympathetic vasomotor tone in hypertension. J Pharmacol Exp Ther. 2007;320:615-626.
Crossref Google Scholar
113

Li DP, Pan HL. Plasticity fo GABAergic control of hypothalamic presympathetic neurons in hypertension. Am J Physiol Heart Circ Physiol. 2006;290:H1110-H1119.
Crossref Google Scholar
114

Ye Z-Y, Li D-P, Byun HS, Li L, Pan H-L. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal-sympathetic drive in hypertension. J Neurosci. 2012;32:8560-8568.
Crossref Google Scholar
115

Orlov SN, Resink TJ, Bernhardt J, Buhler FR. Na+-K+ pump and Na+-K+ co-transport in cultured vascular smooth muscle cells from spontaneously hypertensive rats: baseline activity and regulation. J Hypertens. 1992;10:733-740.
Crossref Google Scholar
116

Jiang G, Cobbs S, Klein JD, O'Neill WC. Aldosterone regulates the Na-K-Cl cotransporter in vascular smooth muscle. Hypertension. 2003;41:1131-1135.
Crossref Google Scholar
117

Orlov SN, Li J-M, Tremblay J, Hamet P. Genes of intracellular calcium metabolism and blood pressure control in primary hypertension. Seminar Nephrol. 1995;15:569-592.
Google Scholar
118
Hamet P, Orlov SN, Tremblay J. Intracellular signalling mechanisms in hypertension. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Treatment. 2 ed. New York: Raven Press; 1995:575-608.
119

Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ. Chloride sensing by WNK1 kinase invoolves inhibition of autophosphorylation. Sci Signal. 2014;7:ra41.
Crossref Google Scholar
120

Gamba G. Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension. Am J Physiol Ren Physiol. 2004;288:F245-F252.
Crossref Google Scholar
121

Ponce-Coria J, San-Cristobal P, Kahle KT, et al. Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases. Proc Natl Acad Sci U. S. A. 2008;105:8458-8463.
Crossref Google Scholar
122

Gamba G. Regulation of NKCC2 activity by SPAK truncated isoforms. Am J Physiol Ren Physiol. 2014;306:F49-F50.
Crossref Google Scholar
123

Bergaya S, Faure S, Baudrie V, et al. WNK1 regulates vasoconstriction and blood pressure response to α1-adrenergic stimulation in mice. Hypertension. 2011;58:439-445.
Crossref Google Scholar
124

Yang S-S, Lo Y-F, Wu C-C, et al. SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol. 2010;21:1868-1877.
Crossref Google Scholar
125

Tang Y, Pacary E, Freret T, et al. Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: identification of potential neuroprotective candidate for stroke. Neurobiol Dis. 2006;21:18-28.
Crossref Google Scholar
126

Friso S, Carvajal CA, Fardella CE, Oliveri O. Epigenetics and arterial hypertension: the challenge of emerging evidence. Transl Res. 2015;165:154-165.
Crossref Google Scholar
127

Orlov SN. NKCC1 as an epigenetically regulated transporter involved in blood pressure elevation with age. Am J Hypertens. 2011;24:1264.
Crossref Google Scholar
128

Janardhan V, Qureshi AI. Mechanisms of ischemic brain injury. Curr Cardiol Rep. 2004;6:117-123.
Crossref Google Scholar
129

Folkow B. Cardiovascular “remodeling” in rat anf human: time axis,extent, and in vivo relevance. Physiology. 2010;25:264-265.
Crossref Google Scholar
130

Liu Y, Gutterman DD. Vascular control in humans: focus on the coronary micocirculation. Basic Res Cardiol. 2009;104:211-227.
Crossref Google Scholar
131

Bidani A, Griffin KA, Williamson G, Wang X, Loutzenhiser R. Protective importance of the myogenic response in the renal circulation. Hypertension. 2009;54:393-398.
Crossref Google Scholar
132

Loutzenhiser R, Bidani AK, Wang X. Systolic pressure and the myogenis response of the afferent arteriole. Acta Physiol Scand. 2004;181:407-413.
Crossref Google Scholar
133

Khodorov B. Clutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones. Prog Biophys Mol Biol. 2004;86:279-351.
Crossref Google Scholar
134

Mongin AA. Disruption of ionic and cell volume homeostasis in cerebral ischemia: the perferct storm. Pathophysiology. 2007;14:183-193.
Crossref Google Scholar
135

Su G, Kintner DB, Sun D. Contribution of Na+,K+,Cl- cotransporter to high-K+o-induced swelling and EAA release is astrocytes. Am J Physiol Cell Physiol. 2002;282:C1136-C1146.
Crossref Google Scholar
136

Busse S, Breder J, Dinkel K, Reymann KG, Schroder UH. Inhibitors of cation-chloride-cotransporters affect hypoxic/hypoglycemic injury in hyppocampal slices. Brain Res. 2005;1946:116-121.
Crossref Google Scholar
137

Su G, Kintner DB, Flagella M, Shull GE, Sun D. Astrocytes from Na+,K+.Cl- cotransporter-null mice exhibit absence of swelling and decrease in EAA release. Am J Physiol Cell Physiol. 2002;282:C1147-C1160.
Crossref Google Scholar
138

Koltsova SV, Luneva OG, Lavoie JL, et al. HC03-dependent impact of Na+,K+,2Cl- cotransport in vascular smooth muscle excitation-contraction coupling. Cell Physiol Biochem. 2009;23:407-414.
Crossref Google Scholar
139

Williams RS, Benjamin IJ. Protective responses in the ischemic myocardium. J Clin Invest. 2000;106:813-818.
Crossref Google Scholar
140

Danielsson J, Yim P, Rinderspacher A, et al. Chloride chanel blockage relaxes airway smooth muscle and potentiates relaxation by ®-agonists. Am J Physiol Lung Cell Mol Physiol. 2014;307:L273-L282.
Crossref Google Scholar
141

Haglund MM, Hochman DW. Furosemide and mannitol suppression of epileptic activity in the human brain. J Neurophysiol. 2005;94:907-918.
Crossref Google Scholar
142

Klomjai W, Lackmy-Vallee A, Katz R, et al. Changes in spinal inhibitory networks induced by furosemide in humans. J Physiol. 2014;592:2865-2879.
Crossref Google Scholar
143

Hannaert P, Alvarez-Guerra M, Pirot D, Nazaret C, Garay RP. Rat NKCC2/NKCC1 cotransport selectivity for loop diuretic drugs. Schmiedeb Arch Pharmacol. 2002;365:193-199.
Crossref Google Scholar
144

Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet. 1999;22:192-195.
Crossref Google Scholar
145

Lang F, Vallon V, Knipper M, Wangemann P. Functional significance of channels and transporters expressed in the inner ear and kidney. Am J Physiol Cell Physiol. 2007;293:C1187-C1208.
Crossref Google Scholar
Genes & Diseases
Volume 2 Issue 2,
June 2015
Pages 186-196
DOI: 10.1016/j.gendis.2015.02.007
Cite this article:
Orlov SN, Koltsova SV, Kapilevich LV, et al. NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension. Genes & Diseases, 2015, 2(2): 186-196. https://doi.org/10.1016/j.gendis.2015.02.007

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Received: 22 December 2014
Accepted: 16 February 2015
Published: 25 February 2015
© 2015, Chongqing Medical University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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