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Increased Serum Concentrations of Human Hepatocyte Growth Factor in Proliferative Diabetic Retinopathy

Department of Clinical and Laboratory Medicine (M.N., M.U., A.N., K.O., M.Y.) and the First Department of Internal Medicine (K.N.), Kyoto Prefectural University of Medicine, Kyoto 602; and the Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University (H.T.), Osaka 570, Japan

Address all correspondence and requests for reprints to: Masato Nishimura, M.D., Department of Clinical and Laboratory Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602, Japan.

	Abstract

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Human hepatocyte growth factor (hHGF) is a powerful inducer of angiogenesis. We investigated the relationship between serum hHGF concentrations and proliferative diabetic retinopathy, the major characteristic of which is retinal neovascularization. Serum hHGF concentrations were measured in diabetic (n = 135) and nondiabetic subjects (n = 80). The mean serum hHGF concentration in diabetic subjects without retinopathy was lower than that in nondiabetic subjects [0.041 ± 0.003 ng/mL (n = 62) vs. 0.080 ± 0.010 ng/mL (n = 80); P < 0.05], but was not different from that in diabetic subjects with background retinopathy (0.058 ± 0.007 ng/mL; n = 26) or preproliferative retinopathy (0.048 ± 0.010 ng/mL; n = 10). The mean serum hHGF concentration was increased in subjects with proliferative retinopathy who had not undergone photocoagulation (0.213 ± 0.025 ng/mL; n = 24), but not in those who had undergone photocoagulation (0.040 ± 0.008 ng/mL; n = 13). Circulating hHGF may be involved in the mechanism of neovascularization in the proliferative diabetic retinopathy, and measurement of serum hHGF may be helpful in predicting the presence of proliferative retinopathy in diabetic subjects.

	Introduction

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PROLIFERATIVE diabetic retinopathy (PDR) is a major cause of adult blindness. Neovascularization is the hallmark of PDR, and until the onset of vitreous hemorrhage, PDR can be completely asymptomatic and can only be detected by examinations of the optic fundus (1). Humoral factors that are able to predict the existence of proliferative retinopathy in diabetic subjects have never been found. Although vitreous levels of insulin-like growth factors I were reportedly elevated in patients with PDR relative to those in controls (2), the association of the serum insulin-like growth factor I concentration with PDR has not been determined (3, 4). Hepatocyte growth factor (HGF), which is identical to scatter factor (5, 6), is a disulfide-linked heterodimeric molecule composed of a 69-kDa kringle-containing -chain and a 34-kDa ß-chain (7, 8). The HGF receptor is the c-met protooncogene product, a transmembrane tyrosine kinase (9). Although HGF has been well characterized as a hepatotropic (10, 11) and a renotropic factor (12, 13) in liver and kidney regeneration, the presence of the local HGF system (HGF and its receptor, c-met) has been demonstrated in both endothelial cells and vascular smooth muscle cells in vivo and in vitro (14). Recent studies indicate that human HGF (hHGF) is a powerful inducer of angiogenesis (15, 16). Moreover, hHGF may contribute to the genesis of acquired immunodeficiency syndrome-associated Kaposi’s sarcoma, a cytokine-dependent neoplasm characterized by a major component of neovascularization (17). Although a relationship between hHGF and neovascularization in PDR has never been reported, hHGF may be involved in the pathogenesis of this disorder. In this study we investigated whether serum hHGF concentrations may indicate the presence of PDR in diabetic patients by studying the relationship between serum concentrations of hHGF and the degree of diabetic retinopathy.

	Subjects and Methods

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One hundred and thirty-five out-patients who had been regularly receiving medical treatment in our hospital for diabetes mellitus were included in this study: 61 men and 74 women (33–86 yr old; mean ± SD age, 63 ± 10 yr). Patients were examined to determine the degree of diabetic retinopathy and treated by specialists in the ophthalmologic department before this investigation; patients were classified as having no diabetic retinopathy (NDR; n = 62), background diabetic retinopathy (BDR; n = 26), preproliferative diabetic retinopathy (Pre-PDR; n = 10), PDR (n = 24), and PDR that had been treated by laser photocoagulation with occurrence of no fresh neovascularization (PC-PDR; n = 13; Table 1). The following definitions were used: BDR consists of microaneurysms, dot and blot hemorrhages, hard exudates, and retinal edema; Pre-PDR consists of cotton-wool spots, venous changes such as dilation, beading, looping, and sausage-like segmentation, arteriolar narrowing, and large dark blot hemorrhages; PDR consists of neovascularization, vitreous changes, and intragel or preretinal hemorrhages. Subjects who had received routine medical examinations at our hospital and who had been found not to have diabetes mellitus, hypertension, or other diseases, including cardiovascular, renal, and hepatic disorders were selected as nondiabetic control subjects (n = 80; 36 men and 44 women; 41–87 yr old; mean age, 62 ± 9 yr). The study protocol was approved by the committee for human research of Kyoto Prefectural University of Medicine, and all subjects provided informed consent for participation. Nurses measured the blood pressure of patients who were in a sitting position in the morning (0900–1100 h) with a standard sphygmomanometer. Blood was collected after an overnight fast, and serum was obtained by centrifugation. Serum concentrations of glucose and uric acid were measured with an automatic analyzer (Ektachem 700 analyzer, Eastman Kodak, Rochester, NY). Serum hemoglobin A_1c was measured by high performance liquid chromatography (Hi-AUTO A1c, HA-8121, Kyoto Daiichi Kagaku Co., Kyoto, Japan). Serum hHGF concentrations were measured by a specific enzyme-linked immunosorbent assay kit (Otsuka Pharmaceutical Co., Tokyo, Japan); the intra- and interassay variations were 2.9% and 2.6%, respectively, and the time difference reproducibility of values in the same person at a 1-week interval was 96.7 ± 9% (n = 20).

Data are expressed as the mean ± SEM. The significance of differences between groups was evaluated by one-way of ANOVA followed by Duncan’s multiple range test. Simple regression analyses were used to assess the relationship between hHGF and other parameters. The criterion for statistical significance was P < 0.05.

	Results

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Diabetic retinopathy and serum hHGF

The mean serum concentration of hHGF was lower in the diabetic patients with NDR than in nondiabetic subjects (0.041 ± 0.003 vs. 0.080 ± 0.010 ng/mL; P < 0.05; Fig. 1). The mean serum hHGF concentration was not different among the diabetic patients of the NDR, BDR (0.058 ± 0.007 ng/mL), and Pre-PDR (0.048 ± 0.010 ng/mL) groups; however, it was higher in the PDR group (0.213 ± 0.025 ng/mL) than in the nondiabetic control subjects or the NDR, BDR, or Pre-PDR group. The mean serum hHGF concentration in the PC-PDR group (0.040 ± 0.008 ng/mL) was lower than that in the PDR group and was at the same level as those in the NDR, BDR, and Pre-PDR groups. Serum hHGF concentrations higher than 0.1 ng/mL were found in 19 of 80 subjects (23.8%) in the nondiabetic control group, 2 of 62 (3.2%) in the NDR group, 3 of 26 (11.5%) in the BDR group, and 17 of 24 (70.8%) in the PDR group, but were not found in any subjects in the Pre-PDR and PC-PDR groups. In addition, serum hHGF concentrations higher than 0.15 ng/mL were not observed in the diabetic patients except in the PDR group, in which serum HGF concentrations were over 0.15 ng/mL in 16 of 24 subjects (66.7%). Serum hHGF concentrations higher than 0.15 ng/mL were observed in 10 of 80 subjects (12.5%) in the nondiabetic control group. In the PDR group, diastolic blood pressure levels were higher (P < 0.05) in the subgroup in which serum hHGF concentrations were below 0.15 ng/mL (84 ± 3 mm Hg; n = 8) than in the subgroup in which serum hHGF levels were above 0.15 ng/mL (75 ± 2 mm Hg; n = 16). Age [64 ± 3 yr (n = 8) vs. 61 ± 3 yr (n = 16)], systolic blood pressure [144 ± 6 mm Hg (n = 8) vs. 138 ± 6 mm Hg (n = 16)], fasting serum glucose concentration [136 ± 19 mg/dL (n = 8) vs. 141 ± 9 mg/dL (n = 16)], serum concentrations of hemoglobin A_1c [8.2 ± 0.4% (n = 8) vs. 7.9 ± 0.3% (n = 16)], and uric acid [4.7 ± 0.5 mg/dL (n = 8) vs. 5.2 ± 0.4 mg/dL (n = 16)] or duration of diabetes [19 ± 2.5 yr (n = 8) vs. 21 ± 1.9 yr (n = 16)] were not different between these two subgroups of PDR.

View larger version (21K): [in this window] [in a new window]   Figure 1. Serum concentrations of hHGF in nondiabetic control subjects (Non DM) and diabetic patients (DM). *, P < 0.05; **, P < 0.01.

In the nondiabetic control group, the serum hHGF concentration was positively correlated with the serum concentration of uric acid, but not with age or blood pressure (Table 2). The serum hHGF concentration was positively correlated with the serum uric acid concentration or the duration of the disease in the diabetic patients without a history of photocoagulation, whereas the serum uric acid concentration was not correlated with serum hHGF in the PC-PDR group.

Diabetes mellitus was treated by diet therapy alone (n = 17), oral antidiabetic drugs [total n = 51; sulfonylurea (n = 40); -glucosidase inhibitor (n = 4), biguanide (n = 1), sulfonylurea plus -glucosidase inhibitor (n = 6)], insulin injection (n = 45), or insulin plus oral antidiabetic drugs [total n = 22; sulfonylurea (n = 12), -glucosidase inhibitor (n = 9), biguanide (n = 1)]. The mean serum hHGF concentration was not different among patients treated with diet (0.037 ± 0.007 ng/mL), oral antidiabetic drugs (0.079 ± 0.014 ng/mL), insulin (0.083 ± 0.013 ng/mL), and insulin plus oral antidiabetic drugs (0.082 ± 0.016 ng/mL).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We showed in this study that the mean serum hHGF concentration in diabetic patients without retinopathy was lower than that in nondiabetic healthy subjects, but diabetic patients with PDR had higher serum hHGF concentrations than diabetic patients with NDR, BDR, or Pre-PDR, or nondiabetic subjects. In contrast, the mean serum hHGF concentration in diabetic patients of PDR with a history of photocoagulation was decreased compared with the values in the PDR group without a history of photocoagulation. The precise mechanism responsible for the low serum hHGF concentrations in diabetic patients with NDR is not clear from this study. Treatment with high concentrations of D-glucose reportedly resulted in a decrease in the hHGF concentration in human aortic endothelial cells, accompanied by an increase in the endothelial concentration of transforming growth factor-ß (TGFß) (18). Because in vitro glucose levels mimicking diabetic hyperglycemia reportedly induce endothelial cell overexpression of TGFß (19, 20), and TGFß inhibits local HGF production (21, 22, 23, 24), TGFß is probably a key factor explaining the low serum hHGF concentrations in the diabetic patients with NDR.

Serum hHGF concentrations in nondiabetic control subjects were distributed over a range between 0.006 and 0.364 ng/mL. Because control subjects were selected carefully in present study, this broad distribution of serum hHGF concentrations does not derive from any medical disorder in control subjects; it may indicate the influence of substances that affect serum hHGF levels, such as a novel serine protease that is responsible for activation of HGF (25). We need further investigation to clarify the regulatory mechanism of the circulating hHGF concentration.

The difference in serum hHGF concentrations between patients with PDR and those with PC-PDR, in which neovascularization subsides, suggests that neovascularization in the retina involves an increase in serum hHGF concentrations in patients with PDR. In vitro, HGF stimulates endothelial migration in Boyden chambers (26) and formation of capillary-like tubules (27). Physiological quantities of purified native mouse HGF and recombinant hHGF have been reported to induce angiogenesis in vivo, and immunoreactive hHGF has been demonstrated in sites surrounding blood vessel formation in psoriatic skin (16). hHGF is likely to be involved in retinal neovascularization, which is a compensatory adaptation for retinal ischemia and a major characteristic of PDR.

The plasma half-life of HGF is reported to be 4 min in rats (28). This rather short half-life and high time difference reproducibility of serum hHGF values in our enzyme-linked immunosorbent assay method (96.7 ± 9%) indicate that hHGF is constitutively secreted into the circulation. Two hypotheses may explain the increased concentrations of serum hHGF in the PDR subjects. One is that hHGF production may be enhanced in extraocular organs such as liver, kidney, lung, or spleen to promote neovascularization in the retina. After 70% partial hepatectomy in rats, HGF messenger ribonucleic acid levels in kidney and spleen increase 3- to 5-fold (29), and HGF messenger ribonucleic acid in spleen is increased after the onset of renal injury caused by unilateral nephrectomy (30). HGF produced in the uninjured organs may be involved in regeneration of liver or kidney through an endocrine mechanism (31). The same endocrinological mechanism may play a role in the increased concentrations of serum hHGF in PDR subjects. Another possibility is that hHGF production may have been enhanced in the eyes of PDR patients. The hHGF concentrations in the human vitreous body are 50- to 100-fold higher than the serum concentrations and are higher in diabetic patients with PDR than in nondiabetic patients (our unpublished observation). Increased concentrations of serum hHGF in PDR patients are likely to originate from enhanced production of hHGF in the eye with neovascularization.

Serum hHGF concentrations were correlated not with age or blood pressure, but with serum concentrations of uric acid in nondiabetic and diabetic subjects, in agreement with our recent observation in healthy subjects (32). No significant correlation of serum hHGF with serum concentrations of hemoglobin A_1c or fasting glucose in diabetic subjects indicates that diabetic control does not necessarily have an influence on serum hHGF concentrations, although hyperglycemia may inhibit the production of hHGF via TGFß, as described above. The significant correlation between serum hHGF and duration of diabetes may reflect the involvement of systemic microvascular complications, including PDR, in serum hHGF concentrations in diabetic subjects, although further studies are needed to clarify this point.

The results in the present study suggest that diabetic patients whose serum hHGF concentrations are over 0.15 ng/mL may have PDR and need detailed ophthalmologic examination, although concentrations of serum hHGF below 0.15 ng/mL do not necessarily exclude the existence of PDR. Moreover, serum hHGF concentrations higher than 0.1 ng/mL in diabetic patients with a history of photocoagulation are likely to suggest the reappearance of retinal neovascularization. Measurement of serum hHGF concentrations may be helpful to predict the presence of PDR in patients with diabetes mellitus.

Received June 23, 1997.

Revised August 19, 1997.

Accepted September 24, 1997.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nishimura, M. Articles by Yoshimura, M. Search for Related Content PubMed PubMed Citation Articles by Nishimura, M. Articles by Yoshimura, M.