Effect of colchicine on cyclosporine nephrotoxicity, reduction of TGF-beta overexpression, apoptosis, and oxidative damage: an experimental animal study.
BACKGROUND
Proinflamatory and profibrotic cytokines may be responsible for the cyclosporine A nephrotoxicity. Increased levels of apoptosis, free oxygen redicals, and transforming growth factor beta (TGF-beta), may play an important roles in the pathogenesis of nephrotoxicity. In this experimental animal study, we sought to investigate the effects of colchicine on the cyclosporine nephrotoxicity.


METHODS
Twenty-four Wistar albino rats were divided into three groups: cyclosporine 15 mg/kg subcutaneously (SC); cyclosporine 15 mg/kg SC plus colchicine 30 mcg/kg orally; and a control group; equal doses of olive oil orally were administered to groups 1, 2, and 3. Renal function, cyclosporine levels, and serum malonyldialdehyde (MDA) levels were measured at the end of 4 weeks. Apoptosis, TGF-beta, and other findings were detected in renal tissue with the TUNEL method, with a immunohistochemical method, and with routine staining procedures, respectively.


RESULTS
There were significant differences in the values of mean creatinine clearance between group 1 and group 3 and between group 2 and group 3 (P < .05 for each comparison), but not between group 1 and group 2 (P > .05). MDA levels in group 1 were high compared with the control group (P < .05) with a trend toward elevation relative to group 2 but the results were not statistically significant (P > .05). Renal tubular vacuolization in group 1 and group 2 animal were greater than in the control group, but no significant difference were observed between any of the groups (P > .05). Mononuclear cell infiltration in group 1 and group 2 hosts were higher than the control group, but there was no significant differences between the groups (P > .05). Afferent arteriolar hyalinization was observed group 1 and 2 but not group 3. There was a statistically significant difference between group 1 and group 3 and between group 2 and group 3 (P < .05 for each comparison). The expression level of TGF-beta was higher in group 1 than group 2 or group 3 (P <.05 for each comparison) but group 2 and group 3 were similar (P > .05). Apoptotic cell death count of group 1 was higher than that in group 2 or group 3 (P < .05, for each comparison); moreover, group 2 also showed greater numbers of apoptotic cells than group 3 (P < .001). At the end of the 4 weeks, there was no intersititial fibrosis in any of the hosts.


CONCLUSIONS
While cyclosporine caused increased TGF-beta expression and apoptotic cell death in the renal tissue of rats colchicine prevented the increase in MDA serum levels, TGF-beta expression, and apoptosis in renal tissue. Our study suggests that colchicine may diminish the cyclosporine nephrotoxicity by its suppressing the expression of TGF-beta, apoptotic cell death, and MDA production.
Disel
U
U
Department of Nephrology, Cukurova University, Medical Faculty, Adana, Turkey.
Paydas
S
S
Dogan
A
A
Gulfiliz
G
G
Yavuz
S
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001160:Arterioles / Q000187:drug effects / Q000473:pathology; D003078:Colchicine / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D023421:Models, Animal; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics*
D016212:Transforming Growth Factor beta; D008315:Malondialdehyde; D016572:Cyclosporine; D003404:Creatinine; D003078:Colchicine