Transgenic mice overexpressing cyclophilin A are resistant to cyclosporin A-induced nephrotoxicity via peptidyl-prolyl cis-trans isomerase activity.
Cyclosporin A (CsA) suppresses immune reaction by inhibiting calcineurin activity after forming complex with cyclophilins and is currently widely used as an immunosuppressive drug. Cyclophilin A (CypA) is the most abundantly and ubiquitously expressed family member of cyclophilins. We previously showed that CsA toxicity is mediated by ROS generation as well as by inhibition of peptidyl-prolyl cis-trans isomerase (PPIase) activity of CypA in CsA-treated myoblasts [FASEB J. 16 (2002) 1633]. Since CsA-induced nephrotoxicity is the most significant adverse effect in its clinical utilization, we here investigated the role of CsA inhibition of CypA PPIase activity in its nephrotoxicity using transgenic mouse models. Transgenic mice of either wild type (CypA/wt) or R55A PPIase mutant type (CypA/R55A), a dominant negative mutant of CypA PPIase activity, showed normal growth without any apparent abnormalities. However, CsA-induced nephrotoxicity was virtually suppressed in CypA/wt mice, but exacerbated in CypA/R55A mice, compared to that of littermates. Also, life expectancy was extended in CypA/wt mice and shortened in CypA/R55A mice during CsA administration. Besides, CsA-induced nephrotoxicity was inversely related to the levels of catalase expression and activity. In conclusion, our data provide in vivo evidence that supplement of CypA PPIase activity allows animal's resistance toward CsA-induced nephrotoxicity.
Hong
Feng
F
Department of Molecular Biology, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Lee
Jinhwa
J
Piao
Yu Ji
YJ
Jae
Yeong Kwon
YK
Kim
Young-Joo
YJ
Oh
Changkyu
C
Seo
Jeong-Sun
JS
Yun
Yeon Sook
YS
Yang
Chul Woo
CW
Ha
Joohun
J
Kim
Sung Soo
SS
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015996:Survival Rate
D000975:Antioxidants; D011994:Recombinant Proteins; D016572:Cyclosporine; D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase