Evolving role of growth factors in the renal response to acute and chronic disease

The roles of growth factors in the pathogenesis of various forms of acute and chronic renal disease are largely putative. Nevertheless, there is a growing body of information that links specific growth factors to particular forms of renal injury. In all instances, it is supposed that such associations are not necessarily unique and that multiple cytokines probably interact to determine the pattern of injury or the regenerative response to such injury. Regeneration of tubular epithelium after acute tubular necrosis involves upregulation of the epidermal growth factor (EGF) receptor. Early studies of exogenously administered EGF indicate that the severity and duration of renal failure may be attenuated by this growth factor. Thus far, the observed responses have been limited and the role of EGF as a therapeutic agent requires more study. The mechanism of generation of tubulointerstitial injury in most forms of renal disease is difficult to understand. Early in vitro studies of growth factor production by tubular cells (in the absence of any infiltrating cells) indicate that platelet-derived growth factor produced by the medullary collecting duct is mitogenic for renal medullary fibroblasts, suggesting a paracrine growth system in this region of the kidney. Insulin-like growth factor I has also been shown to be produced by collecting duct cells. Its production is increased by EGF, and its association with certain forms of renal hypertrophy, i.e., diabetes and hypersomatotrophic states, implies its participation in the hypertrophic growth response. Platelet-derived growth factor is a potent mitogen for glomerular mesangial cells, and its production is regulated by a variety of cytokines. In contrast, transforming growth factor β inhibits cell growth and stimulates extracellular matrix deposition in the glomerulus. Results of early studies with anti-transforming growth factor β antibodies have demonstrated suppression of the pathological changes in an experimental model of proliferative glomerular disease associated with increased transforming growth factor β production. Despite a long-standing search for a growth factor that could act as the initiating stimulus for compensatory renal hypertrophy, no such factor has been found. Indeed, studies of gene expression patterns suggest that hypertrophy is a form of growth that does not share early events with different models of cell proliferation, and the nature of this growth response remains an enigma.