Transforming Growth Factor-beta (TGF-β) との拮抗作用によるHepatocyte Growth Factor (HGF) の抗腎線維化作用の検討

摘要

5/6 nephrectomy (Nx) causes a progressive form of chronic renal injury in rats. However, 5/6 Nx seldom induces severe renal injury in mice, and the reason remains unclear. Transforming growth factor-β(TGF-β) is known as a key cytokine involving in organ fibrosis. Connective tissue growth factor (CTGF) is an important downstream mediator of profibrotic activities of TGF-β. Hepatocyte growth factor (HGF) originally identified as a potent mitogen for hepatocyte has been shown to promote tubule repair following acute renal injury. In renal fibrosis, HGF has been assumed to block profibrotic effects of TGF-β, attenuating renal fibrosis. However, such a counteraction between HGF and TGF-β remains to be determined in detail. Then we investigated the mechanism of the anti-fibrotic effects of HGF on renal fibrosis using the 5/6 Nx model in the wild and TGF-β1 transgenic mice and the co-culture system. In wild type mice, ribonuclease protection assay (RPA) revealed that HGF and TGF-β1 mRNA levels in the remnant kidneys simultaneously increased at 8 hours after the nephrectomy, then decreased, and increased again at week 4 to 12. CTGF andα1(I)procollagen mRNA levels also increased at 8 hours, then decreased, but didnﾕt increased again. In the remnant kidneys of 5/6 Nx mice, endogenous HGF seemed to prevent renal fibrogenesis promoted by TGF-β1. In co-culture system, RPA revealed that TGF-β1 alone could significantly enhance the expression ofα1(I)procollagen mRNA in renal tubulointerstitial fibroblasts (TFB) in the co-culture with renal proximal tubular epithelial cells (PTEC). In contrast, TGF-β1 with HGF did not enhance the expression ofα1(I)procollagen mRNA in TFB in the co-culture. This enhancement was partially because of additional production of CTGF by PTEC stimulated by TGF-β1 in the co-culture. In 5/6 Nx TGF-β1 transgenic mice, excess TGF-β1 caused significant interstitial fibrosis compared to the 5/6 Nx wild mice at week 12. The supplement of recombinant HGF was demonstrated to suppress CTGF expression thereby preventing renal fibrosis.　In conclusion, profibrotic effects of TGF-β1 on TFB was enhanced by the co-existence of PTEC, and HGF can modulate such interaction, resulting in the antifibrotic effects. This anti-fibrotic effect of HGF against TGF-β1 was demonstrated to be mediated by suppressing CTGF mRNA expression in the tubular epithelial cells induced by TGF-β1