The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice.
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.
Leviel
Françoise
F
Centre de recherche des Cordeliers, Université Pierre et Marie Curie, ERL CNRS 7226, INSERM UMRS 872 Equipe 3, Paris, France.
Hübner
Christian A
CA
Houillier
Pascal
P
Morla
Luciana
L
El Moghrabi
Soumaya
S
Brideau
Gaëlle
G
Hassan
Hatim
H
Hatim
Hassan
H
Parker
Mark D
MD
Kurth
Ingo
I
Kougioumtzes
Alexandra
A
Sinning
Anne
A
Pech
Vladimir
V
Riemondy
Kent A
KA
Miller
R Lance
RL
Hummler
Edith
E
Shull
Gary E
GE
Aronson
Peter S
PS
Doucet
Alain
A
Wall
Susan M
SM
Chambrey
Régine
R
Eladari
Dominique
D
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
D027963:Chloride-Bicarbonate Antiporters; C530663:SLC4A8 protein, mouse; D049993:Sodium Chloride Symporter Inhibitors; D027982:Sodium-Bicarbonate Symporters; D006852:Hydrochlorothiazide; D000584:Amiloride; D012964:Sodium
Hypertension. 2004 Dec;44(6):982-7
15477386
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1732-7
9990093
Nat Genet. 2008 May;40(5):592-599
18391953
J Biol Chem. 2001 Mar 16;276(11):8358-63
11133997
Kidney Int. 1996 Jul;50(1):174-83
8807586
JAMA. 2003 May 21;289(19):2560-72
12748199
Am J Physiol Renal Physiol. 2007 Mar;292(3):F914-20
17077386
Am J Physiol Renal Physiol. 2004 Sep;287(3):F404-10
15100097
Am J Physiol. 1989 May;256(5 Pt 2):F957-64
2719125
Am J Physiol. 1982 Jan;242(1):C117-20
7058874
J Clin Invest. 1985 Jul;76(1):132-6
4019771
Kidney Int. 2001 Nov;60(5):1809-23
11703599
Physiol Rev. 1997 Apr;77(2):359-96
9114818
Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2749-53
8464884
J Clin Invest. 1986 Jan;77(1):136-41
3080471
Am J Med Sci. 2000 Jan;319(1):51-62
10653444
Nat Genet. 1998 Jul;19(3):282-5
9662405
Cell. 2001 Feb 23;104(4):545-56
11239411
Nat Genet. 1996 Jun;13(2):183-8
8640224
JAMA. 2002 Dec 18;288(23):2981-97
12479763
J Biol Chem. 1994 Jul 1;269(26):17713-22
8021284
Am J Physiol. 1966 Jun;210(6):1293-8
5923067
Am J Physiol Renal Physiol. 2004 Oct;287(4):F593-601
15345493
Nat Genet. 2006 Oct;38(10):1124-32
16964266
Nat Genet. 2003 Dec;35(4):372-6
14608358
Science. 1991 Jun 28;252(5014):1813-6
2063193
Nat Genet. 2006 Oct;38(10):1105-6
17006464
Am J Physiol. 1995 Dec;269(6 Pt 2):F900-10
8594886
J Physiol. 2001 Feb 1;530(Pt 3):359-66
11158268
Am J Physiol Cell Physiol. 2008 Feb;294(2):C591-603
18077606
Am J Physiol. 1999 Dec;277(6):F974-81
10600945
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9425-30
11459928
Am J Physiol Renal Physiol. 2006 Jun;290(6):F1416-20
16434571
Am J Physiol Renal Physiol. 2001 Dec;281(6):F1021-7
11704552
J Clin Invest. 1995 Nov;96(5):2510-4
7593642
Am J Physiol. 1986 Jun;250(6 Pt 2):F1013-23
3717344
J Biol Chem. 2008 May 9;283(19):12777-88
18319254
Nat Genet. 1996 Jan;12(1):24-30
8528245
Nat Genet. 1996 Mar;12(3):248-53
8589714
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4221-6
11274445
Pharmacol Rev. 1961 Dec;13:517-62
13868749
Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):311-6
18165320
Am J Physiol Renal Physiol. 2002 Apr;282(4):F655-68
11880327
Nature. 1994 Feb 3;367(6462):463-7
8107805
Am J Physiol Cell Physiol. 2006 Oct;291(4):C788-801
16707554
J Am Soc Nephrol. 2004 Sep;15(9):2276-88
15339977
Am J Physiol. 1990 Sep;259(3 Pt 2):F519-28
2396677
Science. 1958 Jan 17;127(3290):146-7
13495490
J Biol Chem. 1992 May 5;267(13):9340-6
1374392
J Biol Chem. 1998 Oct 30;273(44):29150-5
9786924
J Clin Invest. 2003 Aug;112(4):554-65
12925696
Am J Physiol Renal Physiol. 2003 Apr;284(4):F628-43
12620920