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Hepatocyte Growth Factor in the Vitreous Fluid of Patients With Proliferative Diabetic Retinopathy

Its relationship with vascular endothelial growth factor and retinopathy activity

¹ Department of Endocrinology, Hospital General Universitari Vall d’Hebron, Barcelona, Spain
² Department of Ophthalmology, Hospital General Universitari Vall d’Hebron, Barcelona, Spain

Address correspondence to Rafael Simó, MD, Diabetes Unit, Endocrinology Division, Hospital Univesitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail: rsimo{at}hg.vhebron.es

The role of hepatocyte growth factor (HGF) in the etiopathogenesis of proliferative diabetic retinopathy (PDR) remains to be elucidated. Others and we (1–5) have found high intravitreous concentrations of HGF in patients with PDR. However, in these previous reports, the main confounding factors that could lead to misinterpretation of the results (vitreous hemorraghe, intravitreal protein concentration, and plasma HGF levels) have not been fully considered. In the present study, we consider all these confounding factors in order to evaluate the vitreous levels of HGF in patients with PDR and to investigate its relationship with vascular endothelial growth factor (VEGF) and retinopathy activity.

A total of 28 diabetic patients with PDR, in whom a vitrectomy was performed, were included in the study. Thirty nondiabetic patients with other conditions requiring vitrectomy but in whom the retina was not directly affected by neovascularization served as a control group. Patients in whom intravitreous hemoglobin was detectable by spectophotometry were excluded. HGF and VEGF were determined by enzyme-linked immunosorbent assay (R&D Systems, Abingdon, U.K.). The results are expressed as the median and range.

Vitreal levels of both VEGF and HGF were higher in diabetic patients with PDR than in the control group (1.34 [0.16–6.2] vs. 0.009 ng/ml [0.009–0.003] and 19.38 [0.4–80] vs. 6.04 mg/ml [1.8–17.34], respectively, P < 0.0001). These differences remained highly significant after adjusting for serum levels (P < 0.0001). To explore the influence of the breakdown of the blood-retinal barrier and, in consequence, the increased serum diffusion that occurs in PDR patients, the levels of both HGF and VEGF were normalized for total vitreal protein concentration. After correcting for total vitreous protein concentration, the ratio of VEGF-to-vitreal proteins remained significantly higher in diabetic patients with PDR than in the control group (0.34 [0.01–2.3] vs. 0.01 ng/mg [0.003–0.03], respectively, P < 0.0001). However, the ratio of HGF-to-vitreal proteins was lower in diabetic patients than in nondiabetic control subjects (5.03 [2–20] vs. 7.52 ng/mg [1.9–26], P = 0.02). The lower intravitreous levels of HGF obtained after correcting for intravitreal proteins in patients with PDR in comparison with nondiabetic control subjects suggest that serum diffusion largely explains the differences detected in the intravitreous HGF levels between these groups.

The vitreous concentrations of VEGF were higher in patients with active PDR than in patients with quiescent PDR (1.89 [0.2–6.2] vs. 0.78 ng/ml [0.1–1.7], respectively, P = 0.004). By contrast, vitreous HGF was not related to PDR activity (active vs. quiescent, 17.1 [7.3–46.6] vs. 23 ng/ml [0.4–80], respectively, P = NS). Previous studies have found higher HGF concentrations in patients with active PDR than in those with quiescent PDR (1,2). However, after carefully considering the main confounding factors that could lead to a misinterpretation of the results, we did not observe any relationship between PDR activity and intravitreous HGF concentrations.

Finally, we did not find a relationship between intravitreous levels of HGF and VEGF. This was true in absolute terms and after normalizing for vitreal proteins. The different response of HGF and VEGF to hyperglycemia (6) and hypoxia (7) could explain the lack of relationship detected between these growth factors in the vitreous fluid of patients with PDR.

Acknowledgments

This work was supported by grants from the Ministerio de Ciencia y Tecnología (PM99-0136), Instituto Carlos III (G03/212, C03/08), and Novonordisk Pharma (01/0,066)

References

1. 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 21:1759–1763, 1998[Abstract]
   
2. 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 84:659–662, 1999[Abstract/Free Full Text]
   
3. Cantón A, Burgos B, Hernández C, Mateo C, Segura RM, Mesa J, Simó R: Hepatocyte growth factor in vitreous and serum from patients with proliferative diabetic retinopathy. Br J Ophthalmol 84:732–735, 2000[Abstract/Free Full Text]
   
4. Umeda N, Ozaki H, Hayashi H, Kondo H, Uchida H, Oshima K: Non-paralleled increase of hepatocyte growth factor and vascular endothelial growth factor in the eyes with angiogenic and nonangiogenic fibroproliferation. Ophthalmic Res 34:43–47, 2002[Medline]
   
5. Mitamura Y, Takeuchi S, Matsuda A, Tagawa Y, Mizue Y, Nishihira J: Hepatocyte growth factor levels in the vitreous of patients with proliferative vitreoretinopathy. Am J Ophthalmol 129:678–680, 2000[Medline]
   
6. Taniyama Y, Morishita R, Hiraoka K, Aoki M, Nakagami H, Yamasaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T: Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model: molecular mechanisms of delayed angiogenesis in diabetes. Circulation 104:2344–2350, 2001[Abstract/Free Full Text]
   
7. Hayashi S, Morishita R, Nakamura S, Yamamoto K, Moriguchi A, Nagano T, Taiji M, Noguchi H, Matsumoto K, Nakamura T, Higaki J, Ogihara T: Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: downregulation of HGF in response to hypoxia in vascular cells. Circulation 100(Suppl. 19):II301–II308, 1999
   

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