title: Angiotensin II directly stimulates macula densa Na-2Cl-K cotransport via apical AT(1) receptors.
abstract: ANG II is a modulator of tubuloglomerular feedback (TGF); however, the site of its action remains unknown. Macula densa (MD) cells sense changes in luminal NaCl concentration ([NaCl](L)) via a Na-2Cl-K cotransporter, and these cells do possess ANG II receptors. We tested whether ANG II regulates Na-2Cl-K cotransport in MD cells. MD cell Na(+) concentration ([Na(+)](i)) was measured using sodium-binding benzofuran isophthalate with fluorescence microscopy. Resting [Na(+)](i) in MD cells was 27.7 +/- 1.05 mM (n = 138) and increased (Delta[Na(+)](i)) by 18.5 +/- 1.14 mM (n = 17) at an initial rate (Delta[Na(+)](i)/Deltat) of 5.54 +/- 0.53 x 10(-4) U/s with an increase in [NaCl](L) from 25 to 150 mM. Both Delta[Na(+)](i) and Delta[Na(+)](i)/Deltat were inhibited by 80% with 100 microM luminal furosemide. ANG II (10(-9) or 10(-12) M) added to the lumen increased MD resting [Na(+)](i) and [NaCl](L)-dependent Delta[Na(+)](i) and caused a twofold increase in Delta[Na(+)](i)/Deltat. Bath (10(-9) M) ANG II also stimulated cotransport activity, and there was no additive effect of simultaneous addition of ANG II to bath and lumen. The effects of luminal ANG II were furosemide sensitive and abolished by the AT(1) receptor blocker candesartan. ANG II at 10(-6) M failed to stimulate the cotransporter, whereas increased cotransport activity could be restored by blocking AT(2) receptors with PD-123, 319. Thus ANG II may modulate TGF responses via alterations in MD Na-2Cl-K cotransport activity.
authors.affiliation: Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, 35294, USA.
authors.forename: Gergely
authors.initials: G
authors.lastname: Kovács
authors.forename: János
authors.initials: J
authors.lastname: Peti-Peterdi
authors.forename: László
authors.initials: L
authors.lastname: Rosivall
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001713:Biphenyl Compounds; D003600:Cytosol / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D012965:Sodium Chloride / Q000493:pharmacokinetics; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004232:Diuretics; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D028021:Sodium-Potassium-Chloride Symporters; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D012965:Sodium Chloride; D005665:Furosemide; D012964:Sodium; C081643:candesartan