Reciprocal balance of hepatocyte growth factor and transforming growth factor-beta 1 in renal fibrosis in mice

Background. Transforming growth factor-beta 1 (TGF-beta 1) plays a central role in the pathogenesis of renal fibrosis. In contrast, hepatocyte growth factor (HGF) may be an important molecule for tissue repair. As TGF-beta 1 is a suppressor molecule for HGF expression, we asked whether a decrease in HGF expression would be accompanied by an increase in TGF-beta 1 and wheth er the progression of renal fibrosis would be modulated. Methods. We used the ICR strain-derived glomerulonephritis (ICGN) mice as a model of chronic renal disease and examined changes in local HGF expressio n during the natural course of renal fibrosis. To determine the significanc e of intrinsic HGF noted during progression of renal fibrosis, we administe red an anti-HGF antibody to mice at the early stage of renal fibrosis. Results. At an early stage of renal fibrosis, the mice showed strong peritu bular HGF expression, coinciding with tubular proliferation. Tn the late st ages, the renal HGF level was markedly decreased, coinciding with a reducti on in proliferative tubular areas. Renal TGF-beta 1 levels were increased i n accordance with expansion of fibrotic areas. Notably, the anti-HGF antibo dy treatment of early-stage mice decreased the HGF level and reduced tubula r areas, whereas collagen-deposited areas were expanded in parallel with in creased TGF-beta 1 levels. Consequently, in HGF-neutralized mice, there was a rapid progression of renal dysfunction. Conclusions. Not only an increase in TGF-beta 1 level, but also a decrease in local HGF expression may be responsible for the manifestation of renal f ibrosis, particularly tubular destruction.