Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury

Abstract

Hepatocyte growth factor (HGF) has been reported to prevent injury in several models of renal disease; however, whether HGF can also retard progression of established renal disease is not known. The aim of the present study was to examine the effects of HGF on progression of chronic renal disease in rats with remnant kidneys and established injury. Studies were performed in rats that underwent subtotal nephrectomy, were observed for two weeks without therapy, and then randomized to receive HGF or vehicle by continuous infusion for an additional two weeks. HGF administration was associated with a reduction in morphologic evidence of interstitial, but not glomerular injury. The beneficial effects of HGF were not associated with reductions in the expression of transforming growth factor-beta (TGF-beta), or in the extent epithelial cell apoptosis or transdifferentiation. Rather, HGF appeared to induce fibrinolytic pathways by increasing expression of metalloproteinase-9 (MMP-9) and decreasing levels of plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-1 (TIMP-2). HGF administration was also associated with an apparent increase in renal endothelin production and a significant reduction in glomerular capillary pressure. These findings suggest that HGF can retard progression of chronic renal disease even after injury is already established, primarily by promoting matrix degradation.