Protective effects of heme-oxygenase expression in cyclosporine A--induced injury.
Cyclosporine A (CsA) is the immunosuppressant of first choice in allotransplantation. Its use is associated with side effects of nephrotoxicity and neurotoxicity, which are among the most prominent. This study was undertaken to explore whether expression and activity of heme oxygenase (HO), the rate-limiting enzyme in heme degradation, is altered in a rat model of CsA-induced injury. Male Sprague Dawley rats were divided into four groups and treated for 21 days. Group I (control) was injected with olive oil (vehicle), group II with CsA (15 mg/kg/day), group III with CsA and the HO inhibitor stannous mesoporphyrin (SnMP) (30 micromol/kg/day) and group IV with one dose of the HO inducer cobalt protoporphyrin (CoPP) 5 mg/100 or heme (10 mg/kg body weight), three days after onset of CsA treatment. Renal tissue was processed for light microscopy, and for HO-1 enzyme activity, assay and for Western blot analysis. In CsA-treated rats there was histological evidence of tubulointerstitial scarring. HO-1 was undetectable in CsA-treated rats compared to control while there was no change in HO-2. In animals treated with a combination of CsA and SnMP, HO-1 activity was further reduced. In animals treated with a combination of CsA and CoPP, HO-1 protein levels were partially restored. These observations indicate that downregulation of HO-1 expression by CsA could be one mechanism underlying CsA-induced toxicity. The CsA-induced decrease in HO-1 expression is partial and restorable, and attempts to preserve HO levels may attenuate CsA toxicity.
Rezzani
Rita
R
Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy.
Rodella
Luigi
L
Bianchi
Rossella
R
Goodman
Alvin I
AI
Lianos
Elias A
EA
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D018696:Neuroprotective Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D016572:Cyclosporine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2