title: Nitric oxide reduces Cl⁻ absorption in the mouse cortical collecting duct through an ENaC-dependent mechanism.
abstract: Since nitric oxide (NO) participates in the renal regulation of blood pressure, in part, by modulating transport of Na⁺ and Cl⁻ in the kidney, we asked whether NO regulates net Cl⁻ flux (JCl) in the cortical collecting duct (CCD) and determined the transporter(s) that mediate NO-sensitive Cl⁻ absorption. Cl⁻ absorption was measured in CCDs perfused in vitro that were taken from aldosterone-treated mice. Administration of an NO donor (10 μM MAHMA NONOate) reduced JCl and transepithelial voltage (VT) both in the presence or absence of angiotensin II. However, reducing endogenous NO production by inhibiting NO synthase (100 μM N(G)-nitro-L-arginine methyl ester) increased JCl only in the presence of angiotensin II, suggesting that angiotensin II stimulates NO synthase activity. To determine the transport process that mediates NO-sensitive changes in JCl, we examined the effect of NO on JCl following either genetic ablation or chemical inhibition of transporters in the CCD. Since the application of hydrochlorothiazide (100 μM) or bafilomycin (5 nM) to the perfusate or ablation of the gene encoding pendrin did not alter NO-sensitive JCl, NO modulates JCl independent of the Na⁺-dependent Cl⁻/HCO₃⁻ exchanger (NDCBE, Slc4a8), the A cell apical plasma membrane H⁺-ATPase and pendrin. In contrast, both total and NO-sensitive JCl and VT were abolished with application of an epithelial Na(+) channel (ENaC) inhibitor (3 μM benzamil) to the perfusate. We conclude that NO reduces Cl⁻ absorption in the CCD through a mechanism that is ENaC-dependent.
authors.affiliation: Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pech
authors.forename: Monika
authors.initials: M
authors.lastname: Thumova
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Dikalov
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.forename: Susan M
authors.initials: SM
authors.lastname: Wall
mesh_terms: D000042:Absorption / Q000502:physiology; D000450:Aldosterone / Q000008:administration & dosage; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000502:physiology; D027963:Chloride-Bicarbonate Antiporters / Q000502:physiology; D002712:Chlorides / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012964:Sodium / Q000494:pharmacology; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D053503:Epithelial Sodium Channels; D020030:Nitric Oxide Donors; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; C013407:benzamil; D000804:Angiotensin II; D009569:Nitric Oxide; D000450:Aldosterone; D000584:Amiloride; D012964:Sodium; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: cortical collecting duct; nitric oxide; transepithelial voltage