Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease.

Chronic renal disease (CRD) is generally thought to be incurable, except through renal transplantation, and the number of patients with CRD is on the increase. Glomerulosclerosis and tubulointerstitial fibrosis represent the morphological equivalent of end-stage CRD. In this study, we demonstrated the preventive effect of hepatocyte growth factor (HGF) on the progression of renal dysfunction and fibrosis, using a spontaneous mouse model for CRD (ICGN strain). The mice progressively developed glomerular sclerotic injury, tubular atrophy, and renal dysfunction until they were 17 wk of age. When recombinant HGF was injected into these mice during a 4-wk-period (from weeks 14-17 after birth), DNA synthesis of tubular epithelial cells was found to be 4.4-fold higher than in mice without HGF injection, thereby suggesting tubular parenchymal expansion promoted by HGF. Notably, HGF suppressed the expression of transforming growth factor-beta and of platelet-derived growth factor as well as myofibroblast formation in the affected kidney. Consequently, the onset of tubulointerstitial fibrosis was almost completely inhibited by HGF, while HGF attenuated the progression of glomerulosclerosis, both leading to preventing manifestation of renal dysfunction. From our results, supplement therapy with HGF may be taken into consideration as a novel option for prevention and treatment of CRD.

[1]  S. Mizuno,et al.  Angiotensin-Converting Enzyme Inhibitor Suppresses Tubular Expression of Platelet-Derived Growth Factor and Attenuates Progression of Tubulo-Interstitial Fibrosis in a Nephrotic Mouse Model , 1998, Nephron.

[2]  K. Matsumoto,et al.  Simultaneous or delayed administration of hepatocyte growth factor equally represses the fibrotic changes in murine lung injury induced by bleomycin. A morphologic study. , 1997, American journal of respiratory and critical care medicine.

[3]  S. Mizuno,et al.  Diffuse glomerulosclerosis without tubular injury does not directly manifest renal dysfunction in nephrotic mice (ICGN strain). , 1997, Experimental nephrology.

[4]  G. Merlino,et al.  Renal tubular hyperplasia, polycystic disease, and glomerulosclerosis in transgenic mice overexpressing hepatocyte growth factor/scatter factor. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[5]  K. Matsumoto,et al.  Preventive and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis , 1997, Hepatology.

[6]  D. Salant,et al.  RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis , 1997, The Journal of experimental medicine.

[7]  M. Aoki,et al.  Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes , 1997, Diabetes.

[8]  A. Eddy.  Molecular insights into renal interstitial fibrosis. , 1996, Journal of the American Society of Nephrology : JASN.

[9]  E. Imai,et al.  Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats , 1996, Hepatology.

[10]  A. E. El Nahas,et al.  Phenotypic modulation of renal cells during experimental and clinical renal scarring. , 1996, Kidney international. Supplement.

[11]  Y. Kaneda,et al.  Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney , 1996, Nature Medicine.

[12]  D. Lacey,et al.  Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. , 1996, The American journal of pathology.

[13]  C. Alpers,et al.  Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats. , 1996, Kidney international.

[14]  K. Matsumoto,et al.  Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. , 1995, Journal of biochemistry.

[15]  G. Michalopoulos,et al.  The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis , 1995, The Journal of cell biology.

[16]  T. Nakamura,et al.  Differential tubulogenic and branching morphogenetic activities of growth factors: implications for epithelial tissue development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. Remuzzi,et al.  Direct podocyte damage in the single nephron leads to albuminuria in vivo. , 1995, Kidney international.

[18]  M. Noble,et al.  Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros , 1995, The Journal of cell biology.

[19]  W. Border,et al.  Transforming Growth Factor β in Tissue Fibrosis , 1994 .

[20]  T. Nakamura,et al.  Regional expression of hepatocyte growth factor/c-met in experimental renal hypertrophy and hyperplasia. , 1994, The American journal of physiology.

[21]  C. Alpers,et al.  Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury. , 1994, Journal of the American Society of Nephrology : JASN.

[22]  F. Strutz,et al.  On the pathogenesis of chronic renal failure in primary glomerulopathies: a view from the interstitium. , 1994, Experimental nephrology.

[23]  K. Matsumoto,et al.  Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Ueda,et al.  Hepatocyte growth factor and its variant with a deletion of five amino acids are distinguishable in their biological activity and tertiary structure. , 1994, Biochemical and biophysical research communications.

[25]  E. Schmidt,et al.  Hepatocyte growth factor in transgenic mice: Effects on hepatocyte growth, liver regeneration and gene expression , 1994, Hepatology.

[26]  L. Fine,et al.  Loss of glomerular function and tubulointerstitial fibrosis: cause or effect? , 1994, Kidney international.

[27]  Y. Kaneda,et al.  Glomerulosclerosis induced by in vivo transfection of transforming growth factor-beta or platelet-derived growth factor gene into the rat kidney. , 1993, The Journal of clinical investigation.

[28]  C. Birchmeier,et al.  Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development , 1993, The Journal of cell biology.

[29]  Toshikazu Nakamura,et al.  Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo , 1992, Hepatology.

[30]  K. Matsumoto,et al.  Cell density-dependent regulation of albumin synthesis and DNA synthesis in rat hepatocytes by hepatocyte growth factor. , 1992, Journal of biochemistry.

[31]  C. Alpers,et al.  Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor , 1992, The Journal of experimental medicine.

[32]  T. Nakamura,et al.  Hepatocyte growth factor is a paracrine factor for renal epithelial cells: stimulation of DNA synthesis and NA,K-ATPase activity. , 1992, Biochemical and biophysical research communications.

[33]  K. Matsumoto,et al.  Renotropic functions of hepatocyte growth factor in renal regeneration after unilateral nephrectomy. , 1991, The Journal of biological chemistry.

[34]  L. Orci,et al.  Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor , 1991, Cell.

[35]  C. Alpers,et al.  Increased synthesis of extracellular matrix in mesangial proliferative nephritis. , 1991, Kidney international.

[36]  H. Rodemann,et al.  Fibroblasts of rabbit kidney in culture. II. Paracrine stimulation of papillary fibroblasts by PDGF. , 1991, The American journal of physiology.

[37]  T. Nakamura,et al.  Hepatocyte growth factor is a potent mitogen for cultured rabbit renal tubular epithelial cells. , 1991, Biochemical and biophysical research communications.

[38]  K. Tashiro,et al.  Molecular cloning and expression of human hepatocyte growth factor , 1989, Nature.

[39]  M. Okigaki,et al.  Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. , 1989, Biochemical and biophysical research communications.

[40]  W. Keane,et al.  Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. , 1984, Kidney international.

[41]  B. Brenner,et al.  Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. , 1982, The New England journal of medicine.

[42]  H. D. de Wardener,et al.  Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. , 1968, Lancet.

[43]  K. Matsumoto,et al.  Actions of hepatocyte growth factor as a local modulator in the kidney: potential role in pathogenesis of renal disease. , 1998, Kidney international.

[44]  T. Hostetter.  Progression of renal disease and renal hypertrophy. , 1995, Annual review of physiology.

[45]  D. Martin,et al.  Hepatocyte growth factor accelerates recovery from acute ischemic renal injury in rats. , 1994, The American journal of physiology.

[46]  Y. Yamamoto,et al.  Hereditary nephrotic syndrome with progression to renal failure in a mouse model (ICGN strain): clinical study. , 1994, Nephron.