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. 2000 Jul;84(7):732–735. doi: 10.1136/bjo.84.7.732

Hepatocyte growth factor in vitreous and serum from patients with proliferative diabetic retinopathy

A Canton 1, R Burgos 1, C Hernandez 1, C Mateo 1, R Segura 1, J Mesa 1, R Simo 1
PMCID: PMC1723540  PMID: 10873984

Abstract

BACKGROUND—Hepatocyte growth factor (HGF) is an endothelium specific growth factor that has been implicated in angiogenesis, a crucial event for the development of proliferative diabetic retinopathy (PDR). The aim of the study is to determine the intravitreous concentrations of HGF in diabetic patients with PDR, and to investigate whether its serum levels could contribute to its intravitreous concentration.
METHODS—17 diabetic patients and seven non-diabetic patients in whom a vitrectomy was performed were studied. Both groups were matched by serum levels of HGF. Venous blood and vitreous samples were collected simultaneously at the time of vitreoretinal surgery. Vitreous and serum HGF were determined by ELISA.
RESULTS—Intravitreous concentrations of HGF (median and range) were higher in diabetic patients (17.04 ng/ml (9.98-80)) in comparison with non-diabetic patients (5.88 ng/ml (2.57-14.20); p=0.003). Intravitreous HGF concentrations were strikingly higher than serum HGF concentrations both in diabetic patients (17.04 ng/ml (9.98-80) v 0.66 ng/ml (0.26-1.26); p<0.001) and in the control group (5.88 ng/ml (2.57-14.20) v 0.68 ng/ml (0.49-0.96); p=0.003). No correlation was found between serum and vitreous levels of HGF in both groups (diabetic patients, r= −0.31; p=0.5 and control subjects r= −0.15; p=0.5).
CONCLUSION—The high vitreous levels of HGF observed in diabetic patients with PDR cannot be attributed to serum diffusion across the blood-retinal barrier. Therefore, intraocular synthesis appears to be the main contributing factor for the high vitreous HGF concentrations in diabetic patients, a cytokine that seems to be directly involved in the pathogenesis of PDR.



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Figure 1  .

Figure 1  

Diabetic and non-diabetic subjects matched by serum levels of hepatocyte growth factor (HGF). Serum HGF levels in diabetic patients and control subjects were 0.66 ng/ml (0.26-1.26) and 0.68 ng/ml (0.49-0.96), respectively; p=0.45. The horizontal line represents the median.

Figure 2  .

Figure 2  

Vitreous concentrations of hepatocyte growth factor (HGF) in diabetic patients and control subjects with non-diabetic ocular disease. Differences between groups were statistically significant (p=0.003). The horizontal line represents the median.

Figure 3  .

Figure 3  

Lack of relation between serum and vitreous levels of hepatocyte growth factor (HGF) including both diabetic patients and control subjects.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aiello L. P., Avery R. L., Arrigg P. G., Keyt B. A., Jampel H. D., Shah S. T., Pasquale L. R., Thieme H., Iwamoto M. A., Park J. E. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994 Dec 1;331(22):1480–1487. doi: 10.1056/NEJM199412013312203. [DOI] [PubMed] [Google Scholar]
  2. Ashikari S., Habuchi H., Kimata K. Characterization of heparan sulfate oligosaccharides that bind to hepatocyte growth factor. J Biol Chem. 1995 Dec 8;270(49):29586–29593. doi: 10.1074/jbc.270.49.29586. [DOI] [PubMed] [Google Scholar]
  3. Bottaro D. P., Rubin J. S., Faletto D. L., Chan A. M., Kmiecik T. E., Vande Woude G. F., Aaronson S. A. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991 Feb 15;251(4995):802–804. doi: 10.1126/science.1846706. [DOI] [PubMed] [Google Scholar]
  4. Burgos R., Simó R., Audí L., Mateo C., Mesa J., García-Ramírez M., Carrascosa A. Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy. Diabetologia. 1997 Sep;40(9):1107–1109. doi: 10.1007/s001250050794. [DOI] [PubMed] [Google Scholar]
  5. Bussolino F., Di Renzo M. F., Ziche M., Bocchietto E., Olivero M., Naldini L., Gaudino G., Tamagnone L., Coffer A., Comoglio P. M. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol. 1992 Nov;119(3):629–641. doi: 10.1083/jcb.119.3.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gonzatti-Haces M., Seth A., Park M., Copeland T., Oroszlan S., Vande Woude G. F. Characterization of the TPR-MET oncogene p65 and the MET protooncogene p140 protein-tyrosine kinases. Proc Natl Acad Sci U S A. 1988 Jan;85(1):21–25. doi: 10.1073/pnas.85.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Grant D. S., Kleinman H. K., Goldberg I. D., Bhargava M. M., Nickoloff B. J., Kinsella J. L., Polverini P., Rosen E. M. Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1937–1941. doi: 10.1073/pnas.90.5.1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. He P. M., He S., Garner J. A., Ryan S. J., Hinton D. R. Retinal pigment epithelial cells secrete and respond to hepatocyte growth factor. Biochem Biophys Res Commun. 1998 Aug 10;249(1):253–257. doi: 10.1006/bbrc.1998.9087. [DOI] [PubMed] [Google Scholar]
  9. Katsura Y., Okano T., Noritake M., Kosano H., Nishigori H., Kado S., Matsuoka T. Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders. Diabetes Care. 1998 Oct;21(10):1759–1763. doi: 10.2337/diacare.21.10.1759. [DOI] [PubMed] [Google Scholar]
  10. Kulseng B., Børset M., Espevik T., Sundan A. Elevated hepatocyte growth factor in sera from patients with insulin-dependent diabetes mellitus. Acta Diabetol. 1998 Jul;35(2):77–80. doi: 10.1007/s005920050107. [DOI] [PubMed] [Google Scholar]
  11. Lashkari K., Rahimi N., Kazlauskas A. Hepatocyte growth factor receptor in human RPE cells: implications in proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1999 Jan;40(1):149–156. [PubMed] [Google Scholar]
  12. Li Q., Weng J., Mohan R. R., Bennett G. L., Schwall R., Wang Z. F., Tabor K., Kim J., Hargrave S., Cuevas K. H. Hepatocyte growth factor and hepatocyte growth factor receptor in the lacrimal gland, tears, and cornea. Invest Ophthalmol Vis Sci. 1996 Apr;37(5):727–739. [PubMed] [Google Scholar]
  13. Morishita R., Nakamura S., Nakamura Y., Aoki M., Moriguchi A., Kida I., Yo Y., Matsumoto K., Nakamura T., Higaki J. Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes. Diabetes. 1997 Jan;46(1):138–142. doi: 10.2337/diab.46.1.138. [DOI] [PubMed] [Google Scholar]
  14. Naidu Y. M., Rosen E. M., Zitnick R., Goldberg I., Park M., Naujokas M., Polverini P. J., Nickoloff B. J. Role of scatter factor in the pathogenesis of AIDS-related Kaposi sarcoma. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5281–5285. doi: 10.1073/pnas.91.12.5281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nakamura T., Nishizawa T., Hagiya M., Seki T., Shimonishi M., Sugimura A., Tashiro K., Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440–443. doi: 10.1038/342440a0. [DOI] [PubMed] [Google Scholar]
  16. Nakamura T., Teramoto H., Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6489–6493. doi: 10.1073/pnas.83.17.6489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nakamura Y., Morishita R., Higaki J., Kida I., Aoki M., Moriguchi A., Yamada K., Hayashi S., Yo Y., Nakano H. Hepatocyte growth factor is a novel member of the endothelium-specific growth factors: additive stimulatory effect of hepatocyte growth factor with basic fibroblast growth factor but not with vascular endothelial growth factor. J Hypertens. 1996 Sep;14(9):1067–1072. doi: 10.1097/00004872-199609000-00004. [DOI] [PubMed] [Google Scholar]
  18. Nishimura M., Ikeda T., Ushiyama M., Nanbu A., Kinoshita S., Yoshimura M. Increased vitreous concentrations of human hepatocyte growth factor in proliferative diabetic retinopathy. J Clin Endocrinol Metab. 1999 Feb;84(2):659–662. doi: 10.1210/jcem.84.2.5434. [DOI] [PubMed] [Google Scholar]
  19. Nishimura M., Nakano K., Ushiyama M., Nanbu A., Ohtsuka K., Takahashi H., Yoshimura M. Increased serum concentrations of human hepatocyte growth factor in proliferative diabetic retinopathy. J Clin Endocrinol Metab. 1998 Jan;83(1):195–198. doi: 10.1210/jcem.83.1.4499. [DOI] [PubMed] [Google Scholar]
  20. Okada M., Matsumori A., Ono K., Miyamoto T., Takahashi M., Sasayama S. Hepatocyte growth factor is a major mediator in heparin-induced angiogenesis. Biochem Biophys Res Commun. 1999 Feb 5;255(1):80–87. doi: 10.1006/bbrc.1999.0150. [DOI] [PubMed] [Google Scholar]
  21. Paques M., Massin P., Gaudric A. Growth factors and diabetic retinopathy. Diabetes Metab. 1997 Apr;23(2):125–130. [PubMed] [Google Scholar]
  22. Rosen E. M., Goldberg I. D. Regulation of angiogenesis by scatter factor. EXS. 1997;79:193–208. doi: 10.1007/978-3-0348-9006-9_8. [DOI] [PubMed] [Google Scholar]
  23. Rosen E. M., Goldberg I. D. Scatter factor and angiogenesis. Adv Cancer Res. 1995;67:257–279. doi: 10.1016/s0065-230x(08)60715-0. [DOI] [PubMed] [Google Scholar]
  24. Saksela O., Moscatelli D., Sommer A., Rifkin D. B. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J Cell Biol. 1988 Aug;107(2):743–751. doi: 10.1083/jcb.107.2.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shinoda K., Ishida S., Kawashima S., Wakabayashi T., Matsuzaki T., Takayama M., Shinmura K., Yamada M. Comparison of the levels of hepatocyte growth factor and vascular endothelial growth factor in aqueous fluid and serum with grades of retinopathy in patients with diabetes mellitus. Br J Ophthalmol. 1999 Jul;83(7):834–837. doi: 10.1136/bjo.83.7.834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Weng J., Liang Q., Mohan R. R., Li Q., Wilson S. E. Hepatocyte growth factor, keratinocyte growth factor, and other growth factor-receptor systems in the lens. Invest Ophthalmol Vis Sci. 1997 Jul;38(8):1543–1554. [PubMed] [Google Scholar]
  27. Wilson S. E., Walker J. W., Chwang E. L., He Y. G. Hepatocyte growth factor, keratinocyte growth factor, their receptors, fibroblast growth factor receptor-2, and the cells of the cornea. Invest Ophthalmol Vis Sci. 1993 Jul;34(8):2544–2561. [PubMed] [Google Scholar]
  28. Yamaguchi K., Nalesnik M. A., Michalopoulos G. K. Hepatocyte growth factor mRNA in human liver cirrhosis as evidenced by in situ hybridization. Scand J Gastroenterol. 1996 Sep;31(9):921–927. doi: 10.3109/00365529609052003. [DOI] [PubMed] [Google Scholar]
  29. Zarnegar R., Michalopoulos G. K. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol. 1995 Jun;129(5):1177–1180. doi: 10.1083/jcb.129.5.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]

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