FK-506 - EFFECTS ON GLOMERULAR HEMODYNAMICS AND ON MESANGIAL CELLS INCULTURE

FK 506 is a new immunosuppressive drug that, like cyclosporine A (CsA) , presents nephrotoxicity. Glomerular hemodynamic studies showed that acute FK 506 infusion (N = 9, 3 mg/kg body wt, i.v. in bolus) caused a 57% reduction in glomerular filtration rate (GFR) (0.74 +/- 0.03 to 0 .32 +/- 0.02 ml/min, P < 0.05) and a 40% reduction in single nephron g lomerular filtration rate (SNGFR; 43.0 +/- 5.2 to 26.0 +/- 2.5 nl/min, P < 0.05) due to a 25% reduction in glomerular plasma flow rate (Q(A) ) (133.4 +/- 19.8 to 99.8 +/- 12.0 nl/min) and a 22% reduction in glom erular ultrafiltration coefficient (K-f; 0.1009 +/- 0.0203 to 0.0790 /- 0.0130 nl/sec . mm Hg). After 10 days of FK treatment (N = 8, 0.6 m g/kg body wt, i.p.), we observed a reduction of 23% in GFR (0.97 +/- 0 .02 to 0.75 +/- 0.04 ml/min, P < 0.05) and of 23% in SNGFR (37.9 +/- 3 .0 to 29.1 +/- 1.9 nl/min, P < 0.05) due to a 42% reduction in K-f (0. 1486 +/- 0.0101 to 0.0870 +/- 0.0110 nl/sec . mm Hg, P < 0.05) and a 3 8% reduction in Q(A) (117.6 +/- 10.2 to 73.5 +/- 6.1 nl/min, P < 0.05) . The latter was consequent to the increment of 72% in total arteriola r resistance (R(T)) (3.1 +/- 0.2 to 5.2 +/- 0.5 +/- 0.5 10(10) . dyn . sec . cm(-5), P < 0.05). Thus, the pattern of FK 506 effect on glomer ular hemodynamics was similar in both acute and chronic treatments. Ad ditionally, in order to evaluate the effect of FK 506 on mesangial cel ls (MC), we performed studies measuring intracellular calcium concentr ation ([Ca2+](i)) with Fura-2/AM as well as MC contraction by morphome tric analysis. It was observed that FK 506 increases the [Ca2+](i) (R 340/380: 2.5 +/- 0.3 to 3.8 +/- 0.4, P < 0.05) due to mobilization of the extracellular calcium pool, via opening calcium type L voltage dep endent channels, since verapamil blunted the increases of [Ca2+](i) ca used by FK 506 (R 340/380: 3.5 +/- 0.9 to 2.8 +/- 0.8). The [Ca2+](i) was not changed after FK 506 incubation of MC with verapamil and thaps igargin, and thus no calcium release-activated channel (CRAC) was affe cted. The increase of [Ca2+](i) induced by FK 506 probably caused cont raction of MC evaluated by reduction of the cross sectional area from 3772 +/- 106 to 1912 +/- 61 mu m(2) (P < 0.05). Thus, FX 506 caused a reduction in SNGFR by reducing Q(A) and K-f after both acute and chron ic administration, and the mesangial cells potentially participate in this nephrotoxicity via reduction in K-f mainly during chronic treatme nt.