Cyclosporine A enhances vasopressin-induced Ca2+ mobilization and contraction in mesangial cells

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 ± 5.8nM, NS), but 10 µg/ml CsA significantly augmented the 10−8M AVP-induced increase of [Ca2+]i (Δ 94.5 ± 6.6vs. Δ167.3 ± 8.4nM, P < 0.01). This effect was also seen in Ca2+-free medium (P < 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 < 0.01). As compared to control, CsA increased 45Ca2+ uptake in MS cells (7924 ± 414 vs. 11928 ± 760 cpm/mg prot/5 min, P < 0.05); this effect was not affected by the Ca2+ channel blocker verapamil (5 × 10−5M, P < 0.05). MS cell contraction was evaluated by a digital imaging analysis system. With 10−8M AVP 25.7 ± 2.5% of the cells showed a decrease of cell surface area by more than 15%. With AVP + CsA, the percentage of contracting cells increased to 37.3 ± 2.2% (P < 0.01). These results suggest that CsA stimulates transmembrane Ca2+ influx, thereby increasing AVP-sensitive [Ca2+]i stores in MS cells. The effect of CsA to enhance vasoconstrictor-mediated Ca2+ mobilization and contraction in MS cells may contribute to the reduction of the ultrafiltration coefficient (Kf) and, consequently, GFR in CsA nephrotoxicity