The mammalian kidney is susceptible to injury by ischemia/reperfusion and toxins, and regeneration following injury is characterized by hyperplasia and recovery of the damaged epithelial cells lining the tubules. Recent studies have indicated that in response to acute injury, epithelial cells dedifferentiate and become capable of proliferating, and all renal epithelial cells appear to retain the capacity to serve as progenitor cells. Because the response to acute renal failure recapitulates certain aspects of renal ontogeny, investigation of the mechanisms underlying regeneration from acute renal injury may also lead to a better understanding of mechanisms of renal development. Studies have suggested that epidermal growth factor (EGF) or EGF family members may be mediators of renal regeneration following acute injury After either ischemic injury or folic acid nephropathy, 1251-EGF binding increases and administration EGF or TGF-alpha accelerates [3H] thymidine incorporation and recovery of tubular function. However, both preproEGF mRNA levels and urinary EGF levels decrease and remain significantly depressed for up to seven days. We have recently found that acute renal injury significantly increases expression of mRNA and bioactive protein of another member of the BGF-like family of growth factors, heparin-binding epidermal growth factor-like growth factor (HB-EGF). The present studies will continue investigation into characterization of HB-EGF expression in renal injury and will explore potential roles of the growth factor in regeneration of renal epithelia.
The specific aims are: l) to localize time-dependent expression of HB-EGF mRNA and bioactive HB-EGF in acute renal injury and characterize the relationship of HB-EGF expression to specific sites of injury; 2) to examine mechanisms regulating HB-EGF mRNA expression in acute renal injury; 3) to determine mechanisms by which HB-EGF may prevent or minimize renal injury and/or mediate recovery; and 4) to determine whether altering renal HB-EGF levels influences renal response to acute injury. In vivo studies will concentrate upon two models of acute renal injury, ischemia/reperfusion and aminoglycoside nephrotoxicity. Parallel and complementary studies will be performed in cultured renal tubular epithelial cells to explore regulation of expression and actions of HB-EGF in injury. These studies will examine the roles that mediators of acute injury play in expression of HB-EGF mRNA and processing of the precursor peptide. They will also examine potential roles of HB-EGF in recovery from injury both by blocking expression or action of the peptide and by administering exogenous HB-EGF or overexpressing endogenous peptide. Therefore, the overall goal of these studies is to elucidate further the role of EGF-like growth factors in the regulation of regeneration following acute renal injury.
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