title: Colchicine decreases apoptotic cell death in chronic cyclosporine nephrotoxicity.
abstract: Colchicine has been shown to prevent kidney injury in chronic cyclosporine nephrotoxicity; however, the mechanisms of its action are undetermined. The purpose of this study was to clarify whether colchicine prevents cyclosporine-induced kidney injury by decreasing kidney-cell apoptosis. We also sought to determine whether such an antiapoptotic effect was related to Bcl-2/Bax protein and caspase3 activity. Adult male Sprague-Dawley rats kept on a salt-depleted diet (0.05% sodium) were treated daily for 28 days with cyclosporine (15 mg/kg in 1 mL/kg olive-oil vehicle), colchicine (30 microg/kg in 100% ethanol, diluted with sterile saline solution to a final concentration of 30 microg/mL), or both cyclosporine and colchicine. Kidney function, histomorphologic findings, in situ terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end-labeling assay, expressions of Bcl-2 and Bax proteins, and caspase-3 enzymatic activity were compared for the different treatment groups. Compared with the vehicle-treated rats, rats given cyclosporine showed a decline in creatinine clearance rate, an increase in serum creatinine concentration, tubulointerstitial fibrosis, and an increase in the number of apoptotic cells (all P <.01). Concomitant administration of colchicine significantly reversed all the above parameters (all P <.05). The decreased expression of Bcl-2 and the ratio of Bcl-2 to Bax protein seen in cyclosporine-treated rat kidneys were significantly increased after colchicine treatment, accompanying a suppression of caspase-3 activity (P <.05). Furthermore, the decreased apoptotic cell death was closely correlated with improved renal tubulointerstitial fibrosis (r = 0.583, P <.05). These findings strongly suggest that a renoprotective effect of colchicine on cyclosporine-induced nephrotoxicity is coassociated with a decrease in apoptotic cells.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Catholic University of Korea, Korea.
authors.forename: Can
authors.initials: C
authors.lastname: Li
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
authors.forename: Hee Jong
authors.initials: HJ
authors.lastname: Ahn
authors.forename: Wan Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Myung Ja
authors.initials: MJ
authors.lastname: Lee
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Yang
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Byung Kee
authors.initials: BK
authors.lastname: Bang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003078:Colchicine / Q000627:therapeutic use*; D016572:Cyclosporine / Q000097:blood / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000097:blood / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000737:chemistry; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein
chemical_list: C494828:Bax protein, rat; D007166:Immunosuppressive Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D016572:Cyclosporine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003078:Colchicine