The pathological role of Bax in cisplatin nephrotoxicity.
Nephrotoxicity induced by cisplatin involves tubular cell necrosis and apoptosis; the latter of which may be initiated by multiple mechanisms including activation of the intrinsic mitochondrial pathway. In cultured tubular epithelial cells, cisplatin can activate the proapoptotic protein Bax resulting in cytochrome c release, caspase activation, and apoptosis. Definitive evidence for the involvement of Bax in cisplatin nephrotoxicity in vivo, however, is lacking. We analyzed Bax regulation during cisplatin nephrotoxicity in wild-type mice and determined the pathological role of Bax using mice in which this gene was knocked out. In wild-type mice, cisplatin induced Bax in renal tubular cells which became active, accumulated in the mitochondria, and was accompanied by acute kidney injury. Compared with the wild-type mice renal function, as measured by blood urea nitrogen and serum creatinine, was partially but significantly preserved in Bax knockout mice. The number of apoptotic cells was decreased as was general tissue damage. Additionally, cisplatin-induced cytochrome c release was attenuated in the Bax-deficient mice. This significant decrease in apoptosis and in cytochrome c release was also mirrored in primary cultures of proximal tubular cells prepared from Bax knockout animals. Collectively, our results provide compelling evidence for a role of Bax and its related apoptotic pathway in cisplatin nephrotoxicity.
Wei
Q
Q
Department of Cellular Biology and Anatomy, Medical College of Georgia and Veterans Affairs Medical Center, Augusta, Georgia 30912, USA.
Dong
G
G
Franklin
J
J
Dong
Z
Z
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D045304:Cytochromes c / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D003404:Creatinine; D002945:Cisplatin