Apoptosis on Acute Cyclosporine Nephrotoxicity in Rat

Lee, Young Ho; Kim, Nan Hee; Yoon, Jong Woo; Lee, Young Ki; Jo, Sang Kyung; Kim, Yong Sup; Cha, Dae Ryong; Cho, Won Yong; Kim, Aeree; Won, Nam Hee; Ku, Ja Ryong; Kim, Hyoung Kyu

Abstract

OBJECTIVES
Apoptosis is a physiologic or programmed cell death in contrast with necrotic cell death. Recently it has been known that apoptosis are concerned in the effects of chemotherapeutic agents or radiation therapy on tumor cells. Cyclosporine a(CsA), a potent immunosuppressant, has been effectively used in organ transplantaion, but it also has a significant toxicity in the kidneys. However the exact mechanism of CsA nephrotoxicity has not been ellucidated yet. This study was performed to investigate whether apoptosis particiates in CsA nephrotoxicity or not.
METHODS
Twenty seven Sprague-Dawley rats were divided into 5 groups. 1) Vehicle group(n=7) as a control: Cremopbor 50mg/kg/day/subcutaneously (sc) for 7 days, 2) CsA4 group(n=5): CsA 50mg/kg/day/sc for 4 days, 3) CsA7 group(n=5): CsA 50mg/kg/day/sc for 7 days, 4) R4 group(n=5): 4 days after CsA 50mg/kg/day/se for 7 days, and 5) R8 group(n=5): 8 days after CsA 50mg/kg/day/sc for 6 days, Biochemical parameters including blood pressure were measured in each group and the cell count of apoptosis in rat kidney was evaluated by in situ end labelling(ISEL) method.
RESULTS
1) The increase of serum creatinine, blood pressure and decrease of creatinine clearance appeared in CsA4 and CsA7 groups. 2) The ce11 counts of apoptosis on tubular cells in CsA4 and CsA7 groups were significantly increased more than in control group(79.0 +/- 16.9, 98.4 +/- 11.4 vs 35.4 +/- 8.8, p<0.05), and the cell counts of apoptosis on tubular cells in R4 and R8 groups were not significantly different from that in control group(53.8 +/- 12.5, 65.2 +/- 7.1 vs 35.4 +/- 8.8, p>0.05), 3) The cell count of apoptosis on the interstitium in each group was not significantly different from that in control group(p>0.05). 4) The cell count of apaptosis on tubular cells was increased more than that on the interstitium in all groups. 5) The cell count of apoptosis on cortex only in CsA7 group was significantly increased more than that io control group(57.8 +/- 11.5 vs 21.8 +/- 2.6, p<0.05), 6) The cell count of apoptosis on medulla only in CsA4 group was significantly increased more than that in control group(636. +/- 17.9 vs 22.6 +/- 9.7, p<0.05). 7) Total cell counts of apoptosis only in CsA4 and CsA7 groups were significantly increased more than in contral group(96.0 +/- 21.1, 99.8 +/- 11.8 vs 46.6 +/- 11.4, p<0.05).
CONCLUSION
CsA caused apoptosis mainly on tubular cells rather than the interstitial cells and apoptotic cells in CsA nephrotoxicity were not increased during the recovery phase. With the results apoptosis may play an important role in CsA nephrotoxicity.