Inhibition of Chronic Renal Failure by HGF: Mechanistic Study on the HGF-mediated Therapeutic Effects

点击翻译按钮获取中文摘要

It is now widely accepted that HGF is an essential intrinsic repair factor not only in liver but also in parenchymal organs (such as kidney, lung, stomach, skin and so on). Based on these backgrounds, we hypothesized that HGF plays an important role for inhibiting tissue fibrosis, which is characterized by a loss in parenchymal epithelial cells. Actually, we for the first time demonstrated that H GE-induced regeneration of renal epithelial cells leads to prevention of renal interstitial fibrosis, a histopathological hallmark of chronic renal failure. However, it is still unclear: 1) whether HGF reverses fibrotic lesions once the chronic renal injuries are established; and 2) how HGF produces the beneficial effect at a molecular level(s).In the current study, we used streptozotocin-treated mice as a model of diabetic nephropathy to determine physiological and therapeutic effects of HGF on hyperglycemia-induced renal diseases. When the diabetic mice were treated with anti-rodent HGF IgG, … More there were rapid progressions of glomerular hypertrophy/fibrosis and renal dysfunction. Inversely, supplement of exogenous HGF led to improvement in renal function. In this process, HGF initially targeted glomerular mesangial cells and suppressed the high glucose-induced production of TGF-beta1 (a key molecule of renal fibrosis in diabetes), leading to preventions of glomerular fibrosis and proteinuria. Overall, HGF was found to be effective in attenuating diabetic glomerulopathy (characterized by tuft fibrosis, hypertrophy and urinary albumin excretion), even at an advanced stage of diabetes.It is now clear that HGF directly targets glomerular mesangial cells, which are a key player of tuft fibrosis as collagen-producing cells. Thus, we next focused on effect of HGF on glomerular cell behavior. Using anti-Thy-1 IgG-injected rats as an animal model of mesangial proliferative glomerulonephritis, we addressed if HGF may alter proliferative activity in the glomerular mesangial cells. In the anti-Thy-1 IgG-injected rats, mesangial cells newly expressed c-Met/HGF receptor along with trans-differentiation to myofibroblasts. When we administered recombinant HGF protein in the rat model, mesangial cell (i.e., myofibroblast-like) proliferation became faint. ln a culture model, HGF was demonstrated to inhibit PDGF-mediated mesangial cell proliferation, accompanied with suppressed p42 MAPK (Erk) phosphorylation. Consistently with the suppressed myofibroblast proliferation, glomerular fibrotic lesions were suppressed by HGF.Throughout the current experiments, we delineated a new function of HGF to antagonize progression of chronic renal failure: 1) HGF target interstitial myofibroblasts and suppresses TGF-beta1 production; and 2) HGF inhibits PDGF-mediated proliferation of the myofibroblasts, both of which contribute to HGF-mediated anti-fibrotic outcomes in chronic renal diseases. Less