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We conclude that NO modulates cytokine-mediated expression of MMP-9 and TIMP-1 in rat MCs in culture. Our results provide evidence that NO-mediated attenuation of MMP-9 gelatinolytic activity is primarily due to a reduced expression of MMP-9 mRNA, and not the result of direct inhibition of enzymatic activity.

Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435C3 T polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435C3 T and 2677G3 T/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity ( 2 ‫؍‬ 10.5; P ‫؍‬ 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donor's ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P ‫؍‬ 0.034). A dominant role of the donor's ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.

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