Induction of renal endonuclease G by cisplatin is reduced in DNase I-deficient mice.
Nephrotoxicity from the chemotherapeutic drug cisplatin is associated with DNA fragmentation and cell death. We have recently demonstrated that DNase I knockout mice are significantly protected against cisplatin nephrotoxicity, but it is unknown whether the DNA fragmentation that occurs is produced by DNase I or another endonuclease. In this study we assessed the expression of several endonucleases involved in cell death after injection of cisplatin and found that the expression of endonuclease G (EndoG) increased whereas the expression of DNase I decreased almost to zero. Immunostaining showed that some nuclei contained both fragmented DNA and EndoG, suggesting that EndoG may cause DNA fragmentation induced by cisplatin. The increase in expression of EndoG was greater in wild-type mice than in DNase I knockout mice, indicating a potential link between the two endonucleases. In support of such a link, overexpression of DNase I in cultured mouse tubular epithelial cells also induced EndoG. Furthermore, gene silencing of EndoG in vitro provided significant protection against cell death. Taken together, our data suggest that both DNase I and EndoG mediate cisplatin injury to tubular epithelial cells.
Yin
Xiaoyan
X
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Apostolov
Eugene O
EO
Shah
Sudhir V
SV
Wang
Xiaoying
X
Bogdanov
Konstantin V
KV
Buzder
Timea
T
Stewart
Anna G
AG
Basnakian
Alexei G
AG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D019610:Cytoprotection; D053938:DNA Fragmentation / Q000187:drug effects; D003850:Deoxyribonuclease I / Q000172:deficiency* / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D020868:Gene Silencing; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
D000970:Antineoplastic Agents; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D003850:Deoxyribonuclease I; D002945:Cisplatin