Characterization of angiotensin II receptor subtypes in human glomeruli and mesangial cells.
This study was designed to identify the subtypes of angiotensin II (ANG II) receptors present on glomeruli and glomerular mesangial cells and establish their functional significance. Dup 753 and its metabolite EXP 3174, two nonpeptide ANG II-1 receptor (AT1) antagonists, displaced 125I-ANG II and its analogue 125I-[Sar1,Ala8]ANG II from their binding sites in rat and human glomeruli and cultured human mesangial cells, whereas CGP 42112 A and PD 123177, two ANG II-2 receptor (AT2) antagonists, exhibited little displacing activity. Dup 753 and EXP 3174 did not modify the dissociation constant (Kd) value but markedly decreased the number of sites of 125I-[Sar1,Ala8]ANG II binding. The addition of PD 123177 did not further inhibit binding when all AT1 sites were occupied by Dup 753. Binding was markedly reduced by dithiothreitol. EXP 3174 and Dup 753 inhibited the main biological functions of ANG II in mesangial cells including increases in intracellular calcium concentration, PGE2 production, and protein synthesis. PD 123177 was also active but at concentrations 1,000- to 10,000-fold greater than those of AT1 antagonists. These results indicate that 1) only AT1 receptors are present in glomeruli and glomerular mesangial cells; 2) these receptors mediate the functional responses to ANG II; 3) the nonpeptide AT1 antagonists behave as noncompetitive inhibitors; and 4) high concentrations of the nonpeptide AT2 antagonists can recognize AT1 sites.
Chansel
D
D
Institut National de la Santé et de la Recherche Médicale 64, Hôpital Tenon, Paris, France.
Czekalski
S
S
Pham
P
P
Ardaillou
R
R
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism*; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism*; D007700:Kinetics; D007930:Leucine / Q000378:metabolism; D008297:Male; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000378:metabolism*; D014316:Tritium
D011945:Receptors, Angiotensin; D014316:Tritium; D000804:Angiotensin II; D007930:Leucine; D015232:Dinoprostone; D002118:Calcium