The long-term goal of this research is to understand how the kidney recovers from a xenobiotic insult through cell repair and regeneration. Halocarbons produce nephrotoxicity by causing renal proximal tubule cell injury and death. The kidney can recover from halocarbon-induced nephrotoxicity through cell repair and regeneration. Recent studies suggest that halocarbons may also produce renal dysfunction through the inhibition of renal proximal tubule cell regeneration. Investigations into the recovery of renal function following injury and the mechanisms involved in cellular migration, proliferation and differentiation have been severely limited by the lack of in vitro models. Two in vitro models of renal cell injury and regeneration, using primary cultures of rabbit renal proximal tubule cells, have been developed in this laboratory. These models of cell injury and regeneration will be used to examine I.) cellular migration and proliferation following mechanically-and chemically-induced injury and the effects of halocarbons on the ability of cells to migrate and proliferate following mechanically-induced injury, and II.) cellular differentiation in regenerating cells and the mechanisms controlling migration-and proliferation following mechanically- and chemically-induced injury. Specifically, the pathways of renal proximal tubule cell regeneration, the effects of halocarbons on renal proximal tubule cell regeneration following mechanically-induced injury, and the degree of differentiation in regenerating renal proximal tubule cells following mechanically- and halocarbon-induced injury will be determined. Growth factors play a role in the proliferation and differentiation of cells in vitro and in vivo and in the expression of """"""""early response"""""""" genes during proliferation. Therefore, the effect of growth factors, and the role and regulation of the epidermal growth factor receptor in the regeneration and differentiation of renal proximal tubule cells following mechanically- and halocarbon-induced injury will be examined. In addition, the level of expression of """"""""early response"""""""" genes following mechanically- and halocarbon-induced injury to renal proximal tubule cells and during regeneration will be characterized. These studies will contribute to our understanding of the mechanisms involved in renal cell regeneration and the return of normal renal function after injury. Furthermore, the information gained should be applicable to these processes in other tissues.
