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Am J Physiol Renal Physiol 292: F243-F252, 2007. First published August 1, 2006; doi:10.1152/ajprenal.00236.2006 Free Article
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Characterization of cell clones isolated from hypoxia-selected renal proximal tubular cells

Craig Brooks,1 Jinzhao Wang,1 Tianxin Yang,2 and Zheng Dong1

1Department of Cellular Biology and Anatomy, Medical College of Georgia, and Veterans Affairs Medical Center, Augusta, Georgia; and 2Department of Internal Medicine, University of Utah, and Veterans Affairs Medical Center, Salt Lake City, Utah

Submitted 23 June 2006 ; accepted in final form 21 July 2006

Under hypoxia, some cells survive and others are irreversibly injured and die. The factors that determine cell fate under stress remain largely unknown. We recently selected death-resistant cells via repeated episodes of hypoxia. In the present study, 80 clones were isolated from the selected cells and their response to apoptotic injury was characterized. Compared with the wild-type cells, the isolated clones showed a general resistance to apoptosis: 13 were extremely resistant to azide-induced apoptosis, 10 to staurosporine, and 9 to cisplatin. The cell clones that most consistently demonstrated resistance or sensitivity to injury were further studied for their response to azide treatment. Azide induced comparable ATP depletion in these clones and wild-type cells. Hypoxia inducible factor-1 (HIF-1) was upregulated in several clones, but the upregulation did not correlate with cell death resistance. The selected clones maintained an epithelial phenotype, showing typical epithelial morphology, forming "domes" at high density, and expressing E-cadherin. Azide-induced Bax translocation and cytochrome c release, two critical mitochondrial events of apoptosis, were abrogated in death-resistant clones. In addition, cell lysates isolated from these clones showed lower caspase activation on addition of exogenous cytochrome c. Bax, Bak, and Bid expression in these clones was similar to that in wild-type cells, whereas Bcl-2 expression was higher in all the selected clones and, interestingly, Bcl-xL was markedly upregulated in the most death-resistant clones. The results suggest that apoptotic resistance of the selected clones is not determined by a single factor or molecule but, rather, by various alterations at the core apoptotic pathway.

apoptosis; cell death resistance; mitochondria; Bcl-2 proteins


Address for reprint requests and other correspondence: Z. Dong, Dept. of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912 (e-mail: zdong{at}mail.mcg.edu)






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