title: The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice.
abstract: Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloride-sensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na+ and Cl- in mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na+-driven Cl-/HCO3- exchanger (NDCBE/SLC4A8) and the Na+-independent Cl-/HCO3- exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na+ reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice.
authors.affiliation: Centre de recherche des Cordeliers, Université Pierre et Marie Curie, ERL CNRS 7226, INSERM UMRS 872 Equipe 3, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Leviel
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Luciana
authors.initials: L
authors.lastname: Morla
authors.forename: Soumaya
authors.initials: S
authors.lastname: El Moghrabi
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Brideau
authors.forename: Hatim
authors.initials: H
authors.lastname: Hassan
authors.forename: Hassan
authors.initials: H
authors.lastname: Hatim
authors.forename: Mark D
authors.initials: MD
authors.lastname: Parker
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kougioumtzes
authors.forename: Anne
authors.initials: A
authors.lastname: Sinning
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pech
authors.forename: Kent A
authors.initials: KA
authors.lastname: Riemondy
authors.forename: R Lance
authors.initials: RL
authors.lastname: Miller
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Peter S
authors.initials: PS
authors.lastname: Aronson
authors.forename: Alain
authors.initials: A
authors.lastname: Doucet
authors.forename: Susan M
authors.initials: SM
authors.lastname: Wall
authors.forename: Régine
authors.initials: R
authors.lastname: Chambrey
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism*; D004594:Electrophysiology / Q000379:methods; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009865:Oocytes / Q000378:metabolism; D012964:Sodium / Q000737:chemistry*; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism*; D014981:Xenopus
chemical_list: D027963:Chloride-Bicarbonate Antiporters; C530663:SLC4A8 protein, mouse; D049993:Sodium Chloride Symporter Inhibitors; D027982:Sodium-Bicarbonate Symporters; D006852:Hydrochlorothiazide; D000584:Amiloride; D012964:Sodium
references.citation: Hypertension. 2004 Dec;44(6):982-7
references.pmid: 15477386
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1732-7
references.pmid: 9990093
references.citation: Nat Genet. 2008 May;40(5):592-599
references.pmid: 18391953
references.citation: J Biol Chem. 2001 Mar 16;276(11):8358-63
references.pmid: 11133997
references.citation: Kidney Int. 1996 Jul;50(1):174-83
references.pmid: 8807586
references.citation: JAMA. 2003 May 21;289(19):2560-72
references.pmid: 12748199
references.citation: Am J Physiol Renal Physiol. 2007 Mar;292(3):F914-20
references.pmid: 17077386
references.citation: Am J Physiol Renal Physiol. 2004 Sep;287(3):F404-10
references.pmid: 15100097
references.citation: Am J Physiol. 1989 May;256(5 Pt 2):F957-64
references.pmid: 2719125
references.citation: Am J Physiol. 1982 Jan;242(1):C117-20
references.pmid: 7058874
references.citation: J Clin Invest. 1985 Jul;76(1):132-6
references.pmid: 4019771
references.citation: Kidney Int. 2001 Nov;60(5):1809-23
references.pmid: 11703599
references.citation: Physiol Rev. 1997 Apr;77(2):359-96
references.pmid: 9114818
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2749-53
references.pmid: 8464884
references.citation: J Clin Invest. 1986 Jan;77(1):136-41
references.pmid: 3080471
references.citation: Am J Med Sci. 2000 Jan;319(1):51-62
references.pmid: 10653444
references.citation: Nat Genet. 1998 Jul;19(3):282-5
references.pmid: 9662405
references.citation: Cell. 2001 Feb 23;104(4):545-56
references.pmid: 11239411
references.citation: Nat Genet. 1996 Jun;13(2):183-8
references.pmid: 8640224
references.citation: JAMA. 2002 Dec 18;288(23):2981-97
references.pmid: 12479763
references.citation: J Biol Chem. 1994 Jul 1;269(26):17713-22
references.pmid: 8021284
references.citation: Am J Physiol. 1966 Jun;210(6):1293-8
references.pmid: 5923067
references.citation: Am J Physiol Renal Physiol. 2004 Oct;287(4):F593-601
references.pmid: 15345493
references.citation: Nat Genet. 2006 Oct;38(10):1124-32
references.pmid: 16964266
references.citation: Nat Genet. 2003 Dec;35(4):372-6
references.pmid: 14608358
references.citation: Science. 1991 Jun 28;252(5014):1813-6
references.pmid: 2063193
references.citation: Nat Genet. 2006 Oct;38(10):1105-6
references.pmid: 17006464
references.citation: Am J Physiol. 1995 Dec;269(6 Pt 2):F900-10
references.pmid: 8594886
references.citation: J Physiol. 2001 Feb 1;530(Pt 3):359-66
references.pmid: 11158268
references.citation: Am J Physiol Cell Physiol. 2008 Feb;294(2):C591-603
references.pmid: 18077606
references.citation: Am J Physiol. 1999 Dec;277(6):F974-81
references.pmid: 10600945
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9425-30
references.pmid: 11459928
references.citation: Am J Physiol Renal Physiol. 2006 Jun;290(6):F1416-20
references.pmid: 16434571
references.citation: Am J Physiol Renal Physiol. 2001 Dec;281(6):F1021-7
references.pmid: 11704552
references.citation: J Clin Invest. 1995 Nov;96(5):2510-4
references.pmid: 7593642
references.citation: Am J Physiol. 1986 Jun;250(6 Pt 2):F1013-23
references.pmid: 3717344
references.citation: J Biol Chem. 2008 May 9;283(19):12777-88
references.pmid: 18319254
references.citation: Nat Genet. 1996 Jan;12(1):24-30
references.pmid: 8528245
references.citation: Nat Genet. 1996 Mar;12(3):248-53
references.pmid: 8589714
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4221-6
references.pmid: 11274445
references.citation: Pharmacol Rev. 1961 Dec;13:517-62
references.pmid: 13868749
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):311-6
references.pmid: 18165320
references.citation: Am J Physiol Renal Physiol. 2002 Apr;282(4):F655-68
references.pmid: 11880327
references.citation: Nature. 1994 Feb 3;367(6462):463-7
references.pmid: 8107805
references.citation: Am J Physiol Cell Physiol. 2006 Oct;291(4):C788-801
references.pmid: 16707554
references.citation: J Am Soc Nephrol. 2004 Sep;15(9):2276-88
references.pmid: 15339977
references.citation: Am J Physiol. 1990 Sep;259(3 Pt 2):F519-28
references.pmid: 2396677
references.citation: Science. 1958 Jan 17;127(3290):146-7
references.pmid: 13495490
references.citation: J Biol Chem. 1992 May 5;267(13):9340-6
references.pmid: 1374392
references.citation: J Biol Chem. 1998 Oct 30;273(44):29150-5
references.pmid: 9786924
references.citation: J Clin Invest. 2003 Aug;112(4):554-65
references.pmid: 12925696
references.citation: Am J Physiol Renal Physiol. 2003 Apr;284(4):F628-43
references.pmid: 12620920