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

2001; Elsevier BV; Volume: 59; Issue: 6 Linguagem: Inglês

10.1046/j.1523-1755.2001.00717.x

1523-1755

Kunio Matsumoto, Toshikazu Nakamura,

Pancreatic function and diabetes

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-β (TGF-β), a key player in tissue fibrosis. A decrease in endogenous HGF, as well as increase in TGF-β, 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. 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-β (TGF-β), a key player in tissue fibrosis. A decrease in endogenous HGF, as well as increase in TGF-β, 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. α-smooth muscle actin blood urea nitrogen extracellular matrix epidermal growth factor extracellular signal-regulated kinase focal adhesion kinase fibroblast growth factor-1 tacrolimus heparin binding-epidermal growth factor hepatocyte growth factor insulin-like growth factor Madin-Darby canine kidney matrix metalloprotease platelet-derived growth factor prostaglandin E phosphatidylinositol-5-bisphosphate 3-kinase phospholipase C-γ Ras-GTPase activating protein src homology transforming growth factor-β urokinase-type plasminogen activator Animals, including mammals, share the intrinsic ability to regenerate specific tissues and organs. This unique potential to regenerate damaged or lost tissues is a biological defense system, and many therapies depend on the intrinsic regeneration potential (for example, treatment for bone fracture), although this notion often goes unrecognized. Understanding the molecular mechanisms involved in regeneration systems will lead to new clinical strategies to combat renal disease, as is now the case for the immune and neuroendocrine systems. Patterns of tissue regeneration are mainly divided into two distinct systems. One is the “stem cell system.” In tissues, such as nervous and muscle, stem cells usually remain in a quiescent and undifferentiated state (but committed to differentiate into specific cell types), yet they proliferate to produce daughter cells that will differentiate into the required tissues, in response to injuries. The other is a “simple duplication system.” In parenchymal organs such as the kidney and liver, differentiated cells proliferate without dedifferentiation to replace excised or injured tissues. Thus, to understand mechanisms involved in renal and hepatic regeneration, the following issues must be addressed: (1) how differentiated cells recognize injury or partial removal of tissues even though the remaining cells are apparently intact; (2) which tropic factors are responsible for regeneration; and (3) how differentiated cells proliferate and reorganize tissue-specific multicellular architectures. Both the kidney and the liver have a vital capacity to regenerate. After unilateral nephrectomy, a compensatory renal enlargement occurs and blood-borne “renotropin” is present that enhances renal regeneration1.Preuss H.G. Goldin H. A renotropic system in rats.J Clin Invest. 1976; 57: 94-101Crossref PubMed Google Scholar,2.Austin III, H. Goldin H. Preuss H.G. 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