title: Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension.
abstract: We investigated which of the NaCl transporters are involved in the maintenance of salt-sensitive hypertension. Milan hypertensive (MHS) rats were studied 3 mo after birth. In MHS, compared with normotensive strain (MNS), mRNA abundance, quantified by competitive PCR on isolated tubules, was unchanged, both for Na+/H+ isoform 3 (NHE3) and Na+-K+-2Cl- (NKCC2), but higher (119%, n = 5, P < 0.005) for Na+-Cl- (NCC) in distal convoluted tubules (DCT). These results were confirmed by Western blots, which revealed: 1) unchanged NHE3 in the cortex and NKCC2 in the outer medulla; 2) a significant increase (52%, n = 6, P < 0.001) of NCC in the cortex; 3) alpha- and beta-sodium channels [epithelial Na+ channel (ENaC)] unaffected in renal cortex and slightly reduced in the outer medulla, while gamma-ENaC remained unchanged. Pendrin protein expression was unaffected. The role of NCC was reinforced by immunocytochemical studies showing increased NCC on the apical membrane of DCT cells of MHS animals, and by clearance experiments demonstrating a larger sensitivity (P < 0.001) to bendroflumethiazide in MHS rats. Kidney-specific chloride channels (ClC-K) were studied by Western blot experiments on renal cortex and by patch-clamp studies on primary culture of DCT dissected from MNS and MHS animals. Electrophysiological characteristics of ClC-K channels were unchanged in MHS rats, but the number of active channels in a patch was 0.60 +/- 0.21 (n = 35) in MNS rats and 2.17 +/- 0.59 (n = 23) in MHS rats (P < 0.05). The data indicate that, in salt-sensitive hypertension, there is a strong upregulation, both of NCC and ClC-K along the DCT, which explains the persistence of hypertension.
authors.affiliation: Department of Internal Medicine, Chair of Nephrology, Faculty of Medicine, Second University of Napoli, Napoli, Italy. gb.capasso@unina2.it
authors.forename: Giovambattista
authors.initials: G
authors.lastname: Capasso
authors.forename: Maria
authors.initials: M
authors.lastname: Rizzo
authors.forename: Maria Lisa
authors.initials: ML
authors.lastname: Garavaglia
authors.forename: Francesco
authors.initials: F
authors.lastname: Trepiccione
authors.forename: Miriam
authors.initials: M
authors.lastname: Zacchia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mugione
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.forename: Markus
authors.initials: M
authors.lastname: Paulmichl
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.forename: Monique
authors.initials: M
authors.lastname: Carrel
authors.forename: Sara
authors.initials: S
authors.lastname: Damiano
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
authors.forename: Giuliano
authors.initials: G
authors.lastname: Meyer
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism* / Q000503:physiopathology; D007679:Kidney Medulla / Q000378:metabolism* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D049992:Sodium Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D000076988:Sulfate Transporters; D015854:Up-Regulation
chemical_list: D018118:Chloride Channels; D027963:Chloride-Bicarbonate Antiporters; C082118:Clcnka protein, rat; D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; C578716:Slc12a1 protein, rat; C494615:Slc26A4 protein, rat; C000613387:Slc9a3 protein, rat; D049992:Sodium Chloride Symporters; D017673:Sodium Chloride, Dietary; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D000076988:Sulfate Transporters; D000450:Aldosterone