Cyclosporine A enhances vasopressin-induced Ca2+ mobilization and contraction in mesangial cells.
A major problem in cyclosporine A (CsA) therapy is its nephrotoxicity, characterized by a marked fall in glomerular filtration rate (GFR). Since the glomerular ultrafiltration area is an important determinant of GFR and has been proposed to be regulated by mesangial (MS) cell contraction, we examined the effect of CsA on arginine vasopressin (AVP)-induced Ca2+ mobilization and contraction in cultured MS cells. Intracellular Ca2+, [Ca2+]i, concentrations were measured using quin 2. Basal levels were not affected by CsA (151.1 +/- 6.2 vs. 145.2 +/- 5.8 nM, NS), but 10 micrograms/ml CsA significantly augmented the 10(-8) M AVP-induced increase of [Ca2+]i (delta 94.5 +/- 6.6 vs delta 167.3 +/- 8.4 nM, P less than 0.01). This effect was also seen in Ca2+-free medium (P less than 0.01). The effect of CsA on [Ca2+]i was not due to an inhibition of 45Ca2+ efflux, since AVP-induced increase of 45Ca2+ efflux at 30 seconds was enhanced in cells pretreated with CsA (1630 +/- 185 vs. 3646 +/- 197 cpm/mg prot/30 sec, P less than 0.01). As compared to control, CsA increased 45Ca2+ uptake in MS cells (7924 +/- 414 vs. 11928 +/- 760 cpm/mg prot/5 min, P less than 0.05); this effect was not affected by the Ca2+ channel blocker verapamil (5 X 10(-5) M, P less than 0.05). MS cell contraction was evaluated by a digital imaging analysis system.(ABSTRACT TRUNCATED AT 250 WORDS)
Meyer-Lehnert
H
H
Department of Medicine, University of Colorado School of Medicine, Denver.
Schrier
R W
RW
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology*; D004357:Drug Synergism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins; D001127:Arginine Vasopressin; D002118:Calcium