Hepatocyte growth factor prevents chronic allograft dysfunction in liver-transplanted rats

BACKGROUND: Hepatocyte growth factor (HGF) is a growth factor with multiple biologic properties, including mitogenic, morphogenic, anti-apoptotic, and antifibrogenic activities. Long-term administration of the deletion variant of HGF (dHGF) might contribute to the prevention of chronic liver allograft dysfunction, which is attributed to immunologic and nonimmunologic reactions. METHODS: Low-dose tacrolimus was administered to rat-liver recipients after transplantation. Effects of dHGF on transplanted livers treated with low-dose tacrolimus were investigated. RESULTS: Rats receiving liver transplants treated with only low-dose tacrolimus administration showed chronic allograft dysfunction. Treatment with dHGF prolonged the survival time of rats that received liver allografts and suppressed fibrosis of liver allograft. Treatment with dHGF also suppressed the expression levels of interleukin (IL)-1beta, caspase-1, and transforming growth factor (TGF)-beta mRNAs in liver allografts. CONCLUSIONS: The findings indicate that dHGF may prevent chronic liver-allograft dysfunction and thus may become a novel treatment for chronic liver-allograft dysfunction.     

Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy

BACKGROUND: Unilateral ureteral obstruction (UUO) is characterized by progressive tubular atrophy and interstitial fibrosis. Rupture of the balance between cell proliferation and apoptosis plays a critical role in renal atrophy. Hepatocyte growth factor (HGF) is a cytokine function on cell survival and tissue regeneration. We studied the effects and possible mechanisms of HGF gene therapy on tubular cell survival and anti-fibrosis in chronic obstructed nephropathy. METHODS: An in vivo transfection procedure of repeatedly transducing skeletal muscles with the HGF gene using liposomes containing the hemagglutinating virus of Japan (HVJ liposome) was tested on UUO rats. Expression of HGF and c-Met were examined by in situ hybridization, ELISA, or immunohistochemical staining. Interstitial fibrosis and macrophage infiltration were evaluated by Masson's Trichrome staining, alpha-smooth muscle actin and ED-1 immunostaining. Cell survival indices including proliferating cell nuclear antigen (PCNA), Bcl-2, Bcl-xL and Bax were measured by immunohistochemistry and Western blots. Apoptosis was determined by the TUNEL method. RESULTS: After HVJ-HGF gene transfer, endogenous HGF and c-Met were up-regulated in UUO kidneys. Renal fibrosis, macrophage infiltration and tubular atrophy were suppressed both at day 14 and 28 after UUO (P < 0.05 or 0.01). Tubular cell proliferation was activated while apoptosis was inhibited, especially at the late stage of UUO. Bcl-2 was enhanced in the HGF-transfected UUO rats, while no changes of Bcl-xL and Bax were found. CONCLUSIONS: In vivo HGF gene transfection retards the progression of chronic obstructed nephropathy and protects tubular cell survival in the long-term UUO model. Bcl-2 rather than Bcl-xL or Bax may contribute to the anti-apoptotic function of HGF.     

Hepatocyte growth factor prevents the development of chronic allograft nephropathy in rats

Long-term renal isografts in humans and laboratory animals exhibit features similar to those of chronic allograft nephropathy (CAN), indicating that antigen-independent factors, such as acute renal ischemia, are likely to be involved in the development of CAN. Hepatocyte growth factor (HGF) has been demonstrated to play a renotropic role in renal regeneration and protection from acute ischemic injury. This study was thus conducted to investigate the effect of HGF on the development of CAN, using an established rat model. HGF was administered daily (100 microg/d, intravenously) for 4 wk after engraftment. Control animals received saline solution. Allografts from control animals exhibited early evidence of severe structural collapse and necrotic cell death in the proximal tubules and outer medulla, with mononuclear cell infiltration, within 1 wk after engraftment. This was followed by sequential upregulation of adhesion molecules and cytokines, accompanied by dense macrophage infiltration. Fibrogenic events, as indicated by marked increases in transforming growth factor-beta1 expression and the accumulation of smooth muscle alpha-actin, occurred during the same period. Control animals ultimately developed features typical of CAN, with functional deterioration and severe histologic changes; a survival rate of 50.6% by 32 wk was observed. In contrast, remarkably little early injury and no late fibrogenic events were observed for the HGF-treated group. All treated animals survived, with well preserved graft function, during the 32-wk follow-up period. These results indicate that renal protection and recovery from early allograft injury with HGF treatment greatly contribute to a reduction of susceptibility to the subsequent development of CAN in a rat model. The potential application of HGF in the prevention of CAN warrants further attention.     

肝细胞生长因子与男性生殖

肝细胞生长因子(HGF)是一种多效性生长因子,通过与受体c-Met结合后发挥多种生物学效应。本文阐述其生物学特性,并着重强调其与男性生殖的相关性,包括HGF具有促胚胎期睾丸发育、睾丸生精细胞和精子发生、睾丸间质细胞睾酮合成等作用,希望HGF能在男性迟发性性腺功能减退、少弱精子症等男科疾病的治疗方面,提供新的思路与方法,只是目前尚缺乏相关的临床研究。     

Hepatocyte growth factor in human osteoarthritic cartilage

OBJECTIVE: Hepatocyte growth factor/scatter factor is a potent mitogen, morphogen and motogen for a variety of mainly epithelial cells. Hepatocyte growth factor is synthesized by mesenchymal cells and can be found in various tissues. The objective of this study was to investigate the expression and distribution patterns of this pleiotropic growth factor and its receptor, the product of the proto-oncogene c-met in normal and osteoarthritic human knee cartilage. METHODS: Five normal and 14 osteoarthritic human cartilage samples graded histomorphologically by Mankin Score, were studied by radioactive in-situ hybridization and immunohistochemistry for the expression of Hepatocyte growth factor and the c-met receptor. RESULTS: Hepatocyte growth factor could be found by immunohistochemistry in the territorial matrix surrounding the chondrocytes of calcified cartilage and within the deep zone of normal cartilage. Chondrocytes of these cartilage zones showed also positive c-met receptor-staining. Moreover, a small number of chondrocytes in the superficial and intermediate zone showed c-met staining. In accordance with the increased hepatocyte growth factor staining of osteoarthritic cartilage, an enhanced expression of hepatocyte growth factor-RNA by chondrocytes of the deep zone as well as the deeper mid zone was observed. Contrary to normal cartilage, c-met was identified immunohistochemically in osteoarthritic chondrocytes of all cartilage zones. CONCLUSION: These results indicate that hepatocyte growth factor seems to be acting in an autocrine/paracrine manner in normal and osteoarthritic cartilage. The ubiquitous presence of the HGF/HGF-receptor complex in osteoarthritic chondrocytes suggests that hepatocyte growth factor may contribute to the altered metabolism in osteoarthritic cartilage.     

Hepatocyte growth factor: clinical implications in hepatobiliary pancreatic surgery

Hepatocyte growth factor (HGF), originally identified as the most potent mitogen for hepatocytes, is now known to be a cytokine with numerous functions in a wide variety of cells. HGF transduces its various activities via a receptor encoded by the c-met proto-oncogene and coupled to a number of transducers integrating the HGF signal inside the target cells. Extensive investigation has revealed that HGF has various beneficial effects, especially for liver. HGF significantly stimulates regeneration in damaged, as well as in normal liver, ameliorates hepatic fibrosis/cirrhosis; and attenuates various types of liver dysfunction in animals. Moreover, the fascinating data on HGF in experimental liver and islet transplantation suggest that the use of HGF may represent a breakthrough for reducing the shortage of donor livers, and increasing the success rate of insulin independence after islet transplantation. Further understanding of the biological significance of HGF, including that in carcinogenesis, will undoubtedly have important clinical implications in hepatobiliary pancreatic surgery. Received: April 14, 2000 / Accepted: July 20, 2000     

Hepatocyte growth factor in nephronophthisis-medullary cystic disease complex

A 13-year-old Japanese girl presented with severe anemia and renal dysfunction. The nephronophthisis-medullary cystic disease complex was diagnosed from the results of renal biopsy and a family study. Immunohistochemical detection of hepatocyte growth factor in the epithelial cells of dilated renal tubules suggested that it may have a role in the development of the tubular cystic changes which are characteristic of this disease. Received May 16, 1995; received in revised form November 20, 1995; accepted December 12, 1995     

Hepatocyte growth factor receptor in acute tubular necrosis

In acute tubular necrosis, there are early transient increases in circulating and local bioactive hepatocyte growth factor (HGF) levels and renal HGF receptor (c-MET) gene expression. It has therefore been suggested that endogenous HGF may play a role in initiating renal repair. To test this hypothesis, changes in the levels, activity, and anatomic distribution of c-MET protein were characterized in relation to the onset and localization of DNA synthesis in kidneys of rats with ischemia-induced acute tubular necrosis. Whole-kidney c-MET protein levels were significantly increased in the injured kidneys 12 h after injury and rose to a maximum after 1 d, exceeding the control values by sevenfold. Eight days after injury, c-MET levels, although decreasing, were still elevated above control values. An increase in the levels of activated c-MET, i.e., tyrosine-phosphorylated c-MET, was also evident as early as 12 h after injury. Histologic analyses demonstrated that the increase in c-MET immunoreactivity was most marked in the most severely damaged nephron segments in the outer medulla. In injured proximal tubules, the receptor was redistributed from an apical location to an intracellular location. DNA synthesis was increased in the injured kidneys, especially in the outer medulla, where the increase in c-MET protein levels was most prominent. The increase in DNA synthesis was first detected 12 h after the initial increase in activated c-MET levels. It is concluded that the early increases in the levels of c-MET protein and activated receptor support the hypothesis that HGF participates in the initiation of renal regeneration. In addition, the persistent elevation of c-Met protein levels suggests that prolonged and even late treatment with HGF may be of therapeutic value     

Hepatocyte growth factor in hepatic allograft biopsies: an immunohistochemical study

Hepatocyte growth factor (HGF) is a multipotent growth factor that is a powerful stimulator of DNA synthesis in a variety of cell types, especially hepatocytes. This factor is produced by nonparenchymal cells in the liver, presumably Kupffer cells, Ito cells, and sinusoidal endothelial cells. Research has shown that HGF is involved in tissue regeneration, wound healing, normal tissue growth, tumor progression, embryogenesis, and tumor invasion. Elevated serum levels of HGF have been documented in patients with acute renal failure and in renal transplant recipients; however, the importance of HGF in liver transplantation is unknown. The aim of this study was to determine whether induction of HGF expression is associated with acute rejection in liver transplants. We assessed the presence and density of HGF in hepatic allograft biopsy specimens compared with those from a control group of healthy patients.     

肝细胞生长因子对肾保护作用的研究进展

在各种急、慢性肾损伤的疾病中肾间质纤维化是共同的病理改变，其中转化生长因子作为促纤维化细胞生长因子对疾病的发生、发展起重要作用，而肝细胞生长因子可以对抗转化生长因子的促纤维化作用。本文将对肝细胞生长因子在肾脏病中的保护作用进行综述。     

Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases

Hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, has mitogenic, motogenic, anti-apoptotic, and morphogenic (for example, induction of branching tubulogenesis) activities for renal tubular cells, while it has angiogenic and angioprotective actions for endothelial cells. Stromal cells such as mesangial cells, endothelial cells, and macrophages are sources of renal HGF; thus, HGF mediates epithelial-stromal and endothelial-mesangial interactions in the kidney. In response to acute renal injury, the expression of HGF increases in the injured kidney and in distant intact organs such as the lung and spleen. Locally and systemically increased HGF supports renal regeneration, possibly not only by enhancing cell growth but also by promoting morphogenesis of renal tissue. During progression of chronic renal failure/renal fibrosis, the expression of HGF decreases in a manner reciprocal to the increase in expression of transforming growth factor-beta (TGF-beta), a key player in tissue fibrosis. A decrease in endogenous HGF, as well as increase in TGF-beta, augments susceptibility to the onset of chronic renal failure/renal fibrosis. On the other hand, supplements of exogenous HGF have preventive and therapeutic effects in cases of acute and chronic renal failure/renal fibrosis in laboratory animals. HGF prevents epithelial cell death and enhances regeneration and remodeling of renal tissue with injury or fibrosis. A renotropic system underlies the vital potential of the kidney to regenerate, while an impaired renotropic system may confer susceptibility to the onset of renal diseases. Thus, HGF supplementation may be one therapeutic strategy to treat subjects with renal diseases, as it enhances the intrinsic ability of the kidney to regenerate.