Change in renal heme oxygenase expression in cyclosporine A-induced injury.
Cyclosporine A (CsA) is the first immunosuppressant used in allotransplantation. Its use is associated with side effects that include nephrotoxicity. This study explored the anatomic structures involved in CsA nephrotoxicity and the effect of heme oxygenase (HO) in preventing CsA injury. Rats were divided into four groups, which were treated with olive oil, CsA (15 mg/kg/day), CsA plus the HO inhibitor (SnMP; 30 microM/kg/day), and with the HO inducer (CoPP; 5 mg/100 g bw). Renal tissue was treated for morphological, biochemical, and immunohistochemical studies. CsA-treated rats showed degenerative changes with renal fibrosis localized mainly around proximal tubules. Collapsed vessels were sometimes seen in glomeruli. No HO-1 expression and increased expression of endothelin-1 (ET-1) were observed in CsA-treated rats compared with controls. In CsA plus SnMP-treated rats, HO-1 expression was further reduced and the morphology was not changed compared to the CsA group, whereas CsA plus CoPP-treated animals again showed normal morphology and with restoration and an increase in HO-1 levels. HO activity and immunohistochemical data showed similar alterations as HO expression. No changes were observed for HO-2 analysis. The observations indicate that HO-1 downregulation and ET-1 upregulation by CsA might be one mechanism underlying CsA-induced nephrotoxicity. Therefore, attempts to preserve HO levels attenuate CsA nephrotoxicity.
Rezzani
Rita
R
Department of Biomedical Sciences and Biotechnology, Division of Human Anatomy, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. rezzani@med.unibs.it
Rodella
Luigi
L
Buffoli
Barbara
B
Goodman
Alvin A
AA
Abraham
Nader G
NG
Lianos
Elias A
EA
Bianchi
Rossella
R
D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects*; D019332:Endothelin-1 / Q000096:biosynthesis; D004790:Enzyme Induction; D005355:Fibrosis; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D007166:Immunosuppressive Agents; D008665:Metalloporphyrins; D011524:Protoporphyrins; C055421:tin mesoporphyrin; C007095:cobaltiprotoporphyrin; D016572:Cyclosporine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2