title: Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT(1) receptors.
abstract: Angiotensin II (AngII) helps to regulate overall renal tubular reabsorption of salt and water, yet its effects in the distal nephron have not been well studied. The purpose of these studies was to determine whether AngII stimulates luminal Na(+) transport in the cortical collecting duct (CCD). Intracellular Na(+) concentration ([Na(+)](i)), as a reflection of Na(+) transport across the apical membrane, was measured with fluorescence microscopy using sodium-binding benzofuran isophthalate (SBFI) in isolated, perfused CCD segments dissected from rabbit kidneys. Control [Na(+)](i), during perfusion with 25 mM NaCl and a Na(+)-free solution in the bath containing the Na(+)-ionophore monensin (10 microM, to eliminate basolateral membrane Na(+) transport) averaged 19.3 +/- 5.2 mM (n = 16). Increasing luminal [NaCl] to 150 mM elevated [Na(+)](i) by 9.87 +/- 1.5 mM (n = 7; P < 0.05). AngII (10(-9) M) added to the lumen significantly elevated baseline [Na(+)](i) by 6.3 +/- 1.0 mM and increased the magnitude (Delta = 25.2 +/- 3.7 mM) and initial rate ( approximately 5 fold) of change in [Na(+)](i) to increased luminal [NaCl]. AngII when added to the bath had similar stimulatory effects; however, AngII was much more effective from the lumen. Thus, AngII significantly increased the apical entry of Na(+) in the CCD. To determine if this apical entry step occurred via the epithelial Na(+) channel (ENaC), studies were performed using the specific ENaC blocker, benzamil hydrochloride (10(-6) M). When added to the perfusate, benzamil almost completely inhibited the elevations in [Na(+)](i) to increased luminal [NaCl] in both the presence and absence of AngII. These results suggest that AngII directly stimulates Na(+) channel activity in the CCD. AT(1) receptor blockade with candesartan or losartan (10(-6) M) prevented the stimulatory effects of AngII. Regulation of ENaC activity by AngII may play an important role in distal Na(+) reabsorption in health and disease.
authors.affiliation: Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, 35294, USA. petjan@uab.edu
authors.forename: János
authors.initials: J
authors.lastname: Peti-Peterdi
authors.forename: David G
authors.initials: DG
authors.lastname: Warnock
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives*; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001572:Benzofurans; D001713:Biphenyl Compounds; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008856:Microscopy, Fluorescence; D008985:Monensin / Q000494:pharmacology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D012965:Sodium Chloride / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001572:Benzofurans; D001713:Biphenyl Compounds; D007476:Ionophores; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C013407:benzamil; D000804:Angiotensin II; D012965:Sodium Chloride; D000584:Amiloride; D008985:Monensin; D019808:Losartan; C105430:benzofuran; C081643:candesartan