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"calcium switch" model with cultured renal epithelial cells has helped to elucidate some of the critical features of tight junction bioassembly. In this model for tight junction reassembly, signaling events involving G proteins, protein kinase C, and calcium appear necessary for the reestablishment of tight junctions [13-19]. Tight junction injury and recovery, like that which occurs after ischemia and reperfusion, has similarly been modeled by subjecting cultured renal epithelial cells to ATP depletion ("chemical anoxia") followed by repletion. While there are many similarities to the calcium switch, biochemical studies have recently revealed major differences, for example, in the way tight junction proteins interact with the cytoskeleton [12]. Thus, important insights into the basic and applied biology of tight junctions are likely to be forthcoming from further analysis of the ATP depletion-repletion model. Nevertheless, it is likely that, as in the calcium switch model, tight junction reassembly is regulated by classical signaling pathways that might potentially be pharmacologically modulated to enhance recovery after ischemic insults.

More prolonged insults can lead to greater, but still sublethal, injury. Key cellular proteins begin to break down. Many of these (eg, the tight junction protein, occludin, and the adherens junction protein, E-cadherin) are membrane proteins. Matrix proteins and their integrin receptors may need to be resynthesized, along with growth factors and cytokines, all of which pass through the endoplasmic reticulum (ER). The rate-limiting events in the biosynthesis and assembly of these proteins occur in the ER and are catalyzed by a set of ER-specific molecular chaperones, some of which are homologs of the cytosolic heat-shock proteins [20]. The levels of mRNAs for these proteins may increase 10-fold or more in the ischemic kidney, to keep up with the cellular need to synthesize and transport these new membrane proteins, as well as secreted ones.

If the ischemic insult is sufficiently severe, cell death and/or detachment leads to loss of cells from the epithelium lining the kidney tubules. To recover from such a severe insult, cell regeneration, differentiation, and possibly morphogenesis, are necessary. To a limited extent, the recovery of kidney tubule function after such a severe ischemic insult can be viewed as a recapitulation of various steps in renal development. Cells must proliferate and differentiate, and, in fact, activation of growth factor-mediated signaling pathways (some of the same ones involved in kidney development) appears necessary to ameliorate renal recovery after acute ischemic injury [21-30].

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