Ischemic acute renal failure (ARF) is a common clinical syndrome which continues to have a high mortality rate. The early loss of renal proximal tubule (PT) cell polarity and the later tubular cell necrosis are well described is ischemic ARF. However, the mechanism underlying these pivotal events has not yet been elucidated. Based on preliminary data and established role of the newly discovered group of cysteine proteases, the caspases, as mediators of ischemic injury in other organs, we propose that the proinflammatory caspase-1, the """"""""initiator"""""""" caspases 8 and 9 and the """"""""executioner"""""""" caspase-3 8 and 9 and the """"""""executioner"""""""" caspase-3 are activated during ischemic ARF. This causes breakdown of the cytoskeletal protein, spectrin, which leads to dissociation of NaK-ATPase from the basolateral surface of the tubule. In vivo, the significance of these events would be decreased PT reabsorption of sodium, increased distal sodium delivery to the macula densa, increased tubuloglomerular feedback and finally a decreased glomerular filtration rate (GFR). In the first specific aim, using northern blot analysis, immunoblotting and specific fluorogenic substrates, the caspases present in the proximal tubule and activated during ischemia will be identified. In the second specific aim, the importance of caspases as mediators of ischemic ARF will be examined in a renal artery clamp model in rats and mice using specific caspase inhibitors and knockout mice. Renal function and morphological (renal histology) correlates will be documented. The third specific aim will examine the cellular targets of caspases during ischemia using complementary studies in ischemic ARF in vivo, isolated PT in suspension and in vitro. Specifically, the interaction between caspases and the other cysteine protease, calpain, will be studied. Also the effect of ischemic with and without caspases inhibitors will be structured using immunoblotting and immunohistochemistry. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby renal PT damage can lead to the hallmark of ARF, namely the fall in GFR. The relevance of these studies to clinical ARF is substantial and the results should provide leads to altering the course of ischemic ARF.
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