The restoration of function following ischemic acute renal failure (ARF) occurs through a series of events whereby dedifferentiated proximal tubule cells proliferate and migrate into the denuded area of the basement membrane. The loss of differentiated character and the appearance of embryonic markers in the regenerating cells reflect similarities between repair and development. Changes in the renal expressions of several growth factors occur following ARF. Three of them, when administered exogenously to rats rendered ischemic, ameliorate the course of ARF. Consistent with the similarities between repair and development, the same or homologous growth factors are expressed in developing kidney and play key roles in vitro. To determine whether growth factors stimulate the expression of genes in kidney, the products of which are important effectors of the regenerative response, we identified genes, the expressions of which in kidney are enhanced by induction of ARF and further enhanced by the administration of IGF I. One such gene product was identified as osteopontin, suggesting that osteopontin plays an important role in renal regeneration following ARF, and by inference, in development. Accordingly, the specific aims of the present proposal are: l) to define the expression of osteopontin and its binding sites to include the alpha(v)beta(3) integrin and the CD44 receptor in kidneys following induction of ARF in rats; 2) to define the expression of osteopontin and its binding sites in rat kidneys during development; 3) to define the consequences of blocking osteopontin activity on development in vitro and to characterize the mechanism of its effect during the process of recovery following ARF; and 4) to determine whether the administration of osteopontin to rats with ARF ameliorates the course of injury. Our studies will test the hypothesis that the expression of osteopontin in kidney is essential for regeneration following ARF, will shed light on the role of osteopontin and its receptors in this process, will test the hypothesis that osteopontin plays a key role in kidney development, and will provide insight into a novel therapeutic modality that may be useful to treat ARF.
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