Colchicine decreases apoptotic cell death in chronic cyclosporine nephrotoxicity.
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.
Li
Can
C
Division of Nephrology, Department of Internal Medicine, Catholic University of Korea, Korea.
Yang
Chul Woo
CW
Ahn
Hee Jong
HJ
Kim
Wan Young
WY
Park
Cheol Whee
CW
Park
Joo Hyun
JH
Lee
Myung Ja
MJ
Yang
Ji Hye
JH
Kim
Yong-Soo
YS
Bang
Byung Kee
BK
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
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