Viral delivery of superoxide dismutase gene reduces cyclosporine A-induced nephrotoxicity

Abstract

Cyclosporine A (CsA) increases free radical formation in the kidney. Accordingly, this study investigated whether gene delivery of superoxide dismutase (SOD) reduced radical production and nephrotoxicity caused by CsA. Rats were given adenovirus (Ad) carrying lacZ or Cu/Zn-SOD genes three days prior to CsA treatment. Histology, glomerular filtration rates (GFRs) and free radical adducts in urine were assessed. SOD activity was increased 2.5-fold three days after viral infection and remained at 2- and 1.6-fold higher 10 and 17 days later. Treatment with CsA for seven days decreased GFR by 70% in rats infected with Ad-lacZ as expected; however, the decrease was diminished significantly in rats receiving Ad-SOD. CsA treatment for two weeks caused a loss of brush border and dilation of proximal tubules, necrosis, and increased leukocyte infiltration into the kidney; these effects were minimized by SOD. Dimethyl sulfoxide (DMSO) was attacked by the hydroxyl radical to produce a methyl radical. Indeed, administration of CsA with 12C-DMSO in rats infected with Ad-lacZ produced a radical adduct with hyperfine coupling constants similar to 4-POBN/methyl radical adduct and another unknown radical adduct. CsA given with 13C-DMSO produced a 12-line spectrum, confirming the involvement of hydroxyl radicals. Free radical adducts detected in urine were increased approximately fivefold by CsA, an effect blocked completely by SOD. CsA increases free radical formation. Gene delivery of SOD blocks formation of free radicals, thereby minimizing nephrotoxicity caused by CsA.