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1 Department of Cellular Biology and Anatomy and Physiology, Medical College of Georgia, Augusta, Georgia, USA
* To whom correspondence should be addressed. E-mail: zdong{at}mail.mcg.edu.
Bid is a pro-apoptotic Bcl-2 family protein, which upon activation translocates to mitochondria and induces damage to the organelles. Activation of Bid depends on its proteolytic processing into truncated forms of tBid. Bid is highly expressed in the kidneys; however, little is known for its role in renal patho-physiology. In this study, we initially examined Bid activation in cultured rat kidney proximal tubular cells following ATP-depletion. The cells were depleted of ATP by azide incubation in the absence of metabolic substrates, and then returned to normal culture medium for recovery. Typical apoptosis developed during recovery of ATP-depleted cells. This was accompanied by Bid cleavage, releasing tBid of 15 and 13 kD. Bid cleavage was abolished in cells overexpressing Bcl-2, an anti-apoptotic gene. It was also suppressed by caspase inhibitors. Peptide inhibitors of caspase-9 were more effective in blocking Bid cleavage, compared with inhibitors of caspase-8 and caspase-3. Provision of glucose, a glycolytic substrate, during azide incubation inhibited Bid cleavage as well, indicating that Bid cleavage was initiated by ATP-depletion. Consistently, Bid cleavage was also induced following ATP-depletion by hypoxia or mitochondrial uncoupling. Of significance, cleaved Bid translocated to mitochondria, suggesting a role for Bid in the development of mitochondrial defects in ATP-depleted cells. Finally, Bid cleavage was induced during renal ischemia-reperfusion in the rat. Together, these results provide the first evidence for Bid activation in kidney cells following ATP-depletion in vitro and renal ischemia in vivo.
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