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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 683-687
Copyright © 2000 by The Endocrine Society

Original Studies

Is Leptin Associated with Hypertensive Retinopathy?1

Gokhan Uckaya, Metin Ozata, Alper Sonmez, Can Kinalp, Tayfun Eyileten, Necati Bingol, Bayram Koc, Fikri Kocabalkan and I. Caglayan Ozdemir

Departments of Endocrinology and Metabolism (G.U., M.O., I.C.O.) and Internal Medicine (A.S., C.K., T.E., B.K., F.K.), Gulhane School of Medicine, Etlik-Ankara 06018; and Bayindir Medical Center (N.B.), Sogutozu-Ankara 06520, Turkey

Address all correspondence and requests for reprints to: Metin Ozata, M.D., Department of Endocrinology and Metabolism, Gulhane School of Medicine, Etlik-Ankara 06018, Turkey. E-mail: mozata{at}obs.gata.edu.tr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Previous studies have demonstrated that elevated plasma leptin concentrations are associated with essential hypertension. It has also recently been shown that leptin plays a promoting role in angiogenesis, and the vascular endothelium expresses the long form of leptin receptor. Those data led us to hypothesize that leptin might contribute to end-organ damage in hypertension. Thus, in the present study we evaluated the relationship between plasma leptin concentrations and hypertensive retinopathy (HR). One hundred and eleven patients newly diagnosed with essential hypertension [EHT; mean age, 43.5 ± 10.7 yr; body mass index (BMI), 28.1 ± 4.4 kg/m2; male/female ratio, 71/40] and 79 healthy normotensive control subjects (NT; mean age, 43.6 ± 9.2 yr; BMI, 28.2 ± 3.3 kg/m2; male/female ratio, 50/29) were enrolled in the study. For the assessment of retinopathy according to the Keith-Wagener classification, direct and indirect ophthalmoscopy were performed in all subjects after dilatation of the pupils. Plasma leptin levels were significantly higher in EHT (11.8 ± 11.1 ng/mL) than in NT (7.2 ± 5.1ng/mL) (P = 0.003). Plasma leptin concentrations were strongly correlated with BMI in both EHT (r = 0.45; P = 0.001) and NT (r = 0.38; P = 0.001) groups. Plasma leptin in patients with grade 2 HR (24.8 ± 15.8 ng/mL; n = 22) was significantly higher than that in patients with grade 1 HR (16.1 ± 4.9 ng/mL; n = 29; P = 0.001), grade 0 HR (5.1 ± 3.1 ng/mL; n = 60; P = 0.001), and NT (P = 0.001). Plasma leptin in patients with grade 1 HR was also significantly higher than that in patients without retinopathy (P = 0.001) or in NT (P = 0.001). The estimated threshold of plasma leptin concentration for HR was 10.2 ng/mL. This critical leptin level served largely to separate patients with retinopathy from those without retinopathy. In summary, our results show that plasma leptin concentrations increase progressively with higher grades of hypertensive retinopathy even after correction for BMI, suggesting that a critical leptin level is needed for the development of retinopathy. Elevated concentrations of plasma leptin might be secondary to release of leptin by the vascular endothelium damaged by high blood pressure, as an epiphenomenon. However, a pathogenic role for leptin in hypertensive retinopathy cannot be excluded.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESITY IS associated with increased incidence of hypertension and cardiovascular mortality (1, 2, 3). It is known that obesity unfavorably alters lipid and glucose metabolism and facilitates organ injuries, such as arteriosclerosis, retinopathy, and renal dysfunction, in hypertensive subjects (4). The pathophysiological mechanism of hypertensive retinopathy (HR) is not fully established. It is known that the autoregulation of the retinal circulation fails as blood pressure increases beyond a critical limit (5). However, elevated blood pressure alone does not fully account for the extent of retinopathy, as humoral components may be involved as well. Supporting this hypothesis, Lowenthal et al. (6) reported cases in which retinopathy was resolved despite persistence of high blood pressure.

Leptin, a 167-amino acid protein transcribed from the ob gene, was originally cloned in the ob/ob mouse (7). Leptin plays an important role in the regulation of food intake, energy expenditure, and body weight regulation (7). It was shown that the leptin gene is expressed in adipose tissue, gastric epithelium, and placenta (7, 8, 9). Plasma leptin levels correlate with body fat content; it is elevated in obesity (10) and decreased in anorexia nervosa (11). Moreover, it has recently been shown that in addition to its effects on food intake and energy expenditure, leptin influences FSH, LH, ACTH, cortisol, and GH secretion (12, 13, 14, 15). Leptin stimulates hemopoiesis in vitro (16, 17). It has been recently shown that T cells have the signal-transducing leptin receptor and that leptin stimulates the proliferation of CD4+ T cells and increases cytokine production (18).

Previous studies have demonstrated that elevated plasma leptin concentrations are associated with obesity and essential hypertension (19, 20, 21). Increased circulating leptin has been suggested to contribute to increased blood pressure in obesity by activation of the sympathetic nervous system (22). Furthermore, it has recently been shown that the vascular endothelium is a target for leptin action (23, 24), and leptin plays a prominent role in angiogenesis. Sierra-Honigman et al. (24) demonstrated leptin-induced neovascularization in corneas from normal rats; the effect was transduced via its long form receptors in vascular endothelium. Those data led us to hypothesize that leptin might contribute to end-organ damage in hypertension. Thus, in the present study we evaluated the relationship between plasma leptin concentrations and hypertensive retinopathy.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

One hundred and eleven newly diagnosed patients with essential hypertension [EHT; mean age, 43.5 ± 10.7 yr; body mass index (BMI), 28.1 ± 4.4 kg/m2; waist/hip ratio, 0.9 ± 0.07; male/female ratio, 71/40] and 79 healthy normotensive control subjects (NT; mean age, 43.5 ± 9.2 yr; BMI, 28.2 ± 3.3 kg/m2; waist/hip ratio, 0.9 ± 0.09; male/female ratio, 50/29) were enrolled in the study. Patients with hypertension were chosen consecutively. Patients with diabetes mellitus, macroalbuminuria, depression, coronary heart disease, heart failure, and renal failure were not included in the study. Patients who were taking medication and whose body weight had not been stable for at least 3 months were excluded from the study.

Control subjects were selected from a check-up program of 150 hospital staff. They underwent a routine physical and laboratory evaluation to ascertain that they had no hypertension, hyperlipidemia, or psychiatric, metabolic, hepatic, or renal diseases. To obtain a control group, 79 healthy volunteers were chosen to ensure similar BMI, age, and sex distribution as that in the EHT group. The control subjects had no family history of hypertension and diabetes.

The EHT group underwent routine investigations for secondary causes of hypertension and accompanying metabolic, cardiac, hepatic, renal, and psychiatric diseases. All patients were evaluated by standard physical and laboratory examinations. The diagnosis of hypertension was based on the criteria of the sixth report of the National Joint Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (25). Stage 1 and stage 2 hypertensive patients were included in the study. For the retinopathy evaluation, direct and indirect ophthalmoscopy was performed in all subjects after dilatation of the pupils. The fundoscopic examination was performed by a single blinded observer. Grade of hypertensive retinopathy was determined according to the Keith-Wagener classification (26). Only patients with grade 0, 1, and 2 hypertensive retinopathy were included in the study. Patients with grade 3 and 4 hypertensive retinopathy and stage 3 hypertension were not included, because most had complications that could influence the plasma leptin levels. All subjects gave informed consent for participating in the study. The study was approved by the ethical committee of Gulhane School of Medicine.

Methods

Arterial blood pressure was measured in the right arm by mercury sphygmomanometer three times in a resting condition in the morning, and mean values were calculated for diastolic and systolic pressures. Fasting blood samples were collected and promptly centrifuged, and the plasma was stored at -70 C until leptin assay was performed. All samples were run in the same assay.

Laboratory procedures

Plasma leptin concentrations were measured in duplicate by RIA (Human Leptin RIA Kit, Linco Research, Inc., St. Charles, MO). The assay had a sensitivity of 0.5 ng/mL, with an intraassay coefficient of variation of 8.3% (n = 5) at 4.9 ng/mL and 3.4% (n = 5) at 25.6 ng/mL.

Data analysis

Results are reported as the mean ± SD. The Kolmogorov-Smirnov test was used to evaluate the distribution characteristics of the variables. Differences between EHT and NT groups were tested for significance by Mann-Whitney U test. The relationship between variables was analyzed by Spearman’s correlation. The results were also analyzed by one-way ANOVA test and post-hoc Tamhane’s T2 test for comparison of subgroups. BMI-adjusted leptin levels were estimated for each subgroup, and the significance between groups was determined by analysis of covariance. Straight regression lines of BMI and plasma leptin concentrations were compared using large sample Z test for parallelism. Receiver operating characteristics curve analysis was performed to determine a threshold level of leptin for HR. Differences and correlations were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical and laboratory data for the patient and control groups are shown in Table 1Go. No significant differences in age, waist/hip ratio, or BMI were detected between EHT and NT groups. However, the plasma leptin concentrations were significantly higher in the EHT than the NT group (P = 0.003). There was no significant correlation between plasma leptin and systolic or diastolic blood pressure (r = 0.07 and r = 0.04, respectively; both P > 0.05). Plasma leptin levels were strongly correlated with BMI in EHT (r = 0.45; P = 0.001) and NT (r = 0.38; P = 0.001; Fig. 1Go). The intercepts and slopes of the regression lines were significantly different between the groups (by one-tailed Z test for parallelism: Z = 1.679; P = 0.047). As shown in Table 2Go and Fig. 2Go, patients were subdivided into three groups according to severity of retinopathy. Plasma leptin in patients with grade 2 HR (n = 22; 24.8 ± 15.8 ng/mL) was significantly higher than that in patients with grade 1 HR (n = 29; 16.1 ± 4.9 ng/mL; P = 0.001) or patients with grade 0 HR (n = 60; 5.1 ± 3.1 ng/mL; P = 0.001). Plasma leptin in patients with grade 1 HR also significantly differed from that in patients without retinopathy (P = 0.001). Although there was a tendency of increased BMI accompanying the severity of retinopathy, there were no significant differences in BMI between grade 2 and grade 1 HR groups (P = 0.27; Table 2Go). However, BMI in grade 2 HR was higher than that in grade 0 HR (P < 0.001). Leptin concentrations in subgroups adjusted for BMI were still significantly different (P < 0.001; Table 2Go). A threshold level of leptin for the existence of HR was obtained by receiver operating characteristics curve analysis. The estimated threshold of plasma leptin for HR was 10.2 ng/mL (sensitivity, 84%; specificity, 82%; area under the curve, 0.825; P = 0.001).


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  		Table 1. Clinical and laboratory features of the patient and control groups

 


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  		Figure 1. BMI and plasma leptin levels of patients with EHT (r = 0.45; P = 0.001) and NT (r = 0.38, P = 0.001). Estimation results of trend lines are leptin = 1.35 (BMI) - 25.9 for patients and leptin = 0.6 BMI - 9.6 for controls. The intercepts and slopes of the regression lines were significantly different between the groups (by one-tailed Z test for parallelism: Z = 1.679; P = 0.047).

 

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  		Table 2. Characteristics of patients according to the retinopathy grade

 


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  		Figure 2. Mean plasma leptin levels according to severity of hypertensive retinopathy. Error bars indicate 95% confidence limits.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In support of our findings, Agata et al. (19), and Suter et al. (20) also demonstrated high plasma leptin concentrations in essential hypertension. Recently, Shorr et al. (21) showed that normotensive young males with a positive family history of hypertension had higher plasma leptin levels than controls without a family history of hypertension, emphasizing that leptin expression is affected by the genetic background of hypertension. Leptin has multiple actions that are potentially relevant not only to control of body fat, but also to cardiovascular regulation (22). Leptin may be involved in cardiovascular functions through its central nervous system effects. Dunbar et al. (27) demonstrated that intracerebroventricular administration of leptin progressively increases mean arterial pressure. Moreover, Shek et al. (28) reported that infusion of recombinant leptin via a peripheral vein increases arterial pressure and heart rate in rats. However, a lower infusion rate via the carotid artery resulted in similar alterations in blood pressure and heart rate. More recently, Villarreal et al. (29) demonstrated that exogenous leptin has a significant natriuretic effect in the normal rat and a blunted saluretic response in hypertension and obesity. All of these observations emphasize the effect of leptin on arterial pressure.

The main finding of the present study is that plasma leptin levels were increased in parallel to the severity of hypertensive retinopathy even after correction for BMI. Although there is a trend toward increasing BMI with increasing severity of retinopathy, there was no significant difference in BMI between grade 2 and grade 1 HR groups in our study. Moreover, leptin levels were still significantly different among groups after correction for BMI. Thus, it appears that the relationship between plasma leptin levels and retinopathy is not simply dependent on changes in BMI. Moreover, we assessed the predictive value of leptin for occurrence of HR. The critical leptin level was in the range of 10.2 ng/mL. This level served to largely separate patients with HR from patients without retinopathy. Evidently a given leptin concentration is essential for HR.

Severe systemic hypertension has long been recognized as a cause of various changes in the retinal vasculature of the eye (30, 31). Although changes in blood pressure regulate retinal blood flow, autoregulation becomes ineffective when the blood pressure rises or falls beyond certain limits. It has been shown that with a rise of blood pressure 40–60% above the resting awake level, autoregulation of cerebral flow may fail (32). With a severe rise of blood pressure, the autoregulation breaks down in retinal vasculature, resulting in focal or generalized dilatation of arterioles. Morphological studies of the dilated segments revealed endothelial cell dysfunction and endothelial cell loss. These changes result in the failure of the blood-retina barrier and increased permeability (5). Systemic or local actions of humoral agents, such as angiotensin II, could be involved in the vascular injury of high blood pressure as well (33). We recently found that plasma leptin is strongly correlated with PRA in patients with essential hypertension (34). Lembo et al. reported that leptin increases the production of endothelial nitric oxide in isolated blood vessels (35). It is tempting to speculate that an endothelial vasorelaxant effect of leptin may constitute a contraregulatory mechanism opposing a vasoconstrictor and pressor effect of leptin mediated via sympathetic excitation (36, 37). Little is known about the mechanisms involved in the evolution of HR, but recent data suggest that the retina may be an important target for leptin action, although leptin has not yet been shown to be expressed in the retinal tissue. Recently, Bouloumie et al. (23) reported that leptin promotes angiogenesis in human umbilical venous and porcine aortic endothelial cells. Concomitantly, Sierra-Honigmann et al. (24) showed that leptin stimulates in vivo angiogenesis in the rat cornea. Both studies indicate that leptin generates an angiogenic effect via activation of endothelial long form leptin receptors. Taken together, it can be speculated that leptin contributes to the pathophysiological mechanisms underlying hypertensive retinopathy. The importance of this finding is that this new target for leptin action may lead to novel pharmacological strategies with the use of leptin antagonists in the treatment of HR.

Here we found no correlation between plasma leptin concentrations and blood pressure. This suggests that plasma leptin is not a primary factor in the regulation of blood pressure. Previous studies reported contradictory results. Agata et al. (19) claimed that both patients with hypertension and normotensive controls had a positive correlation between plasma leptin and mean blood pressure, whereas in the study by Suter et al. (20) a positive correlation between plasma leptin and systolic blood pressure existed only in hypertensive women and normotensive men. In contrast, neither Lonnqvist et al. (38) nor Mohamed-Ali et al. (39) found a correlation between blood pressure and plasma leptin levels. More recently, Narkiewicz et al. found that plasma leptin is significantly correlated with heart rate and diastolic pressure, but not with 24-h ambulatory systolic blood pressure in 60 men with essential hypertension (40).

In summary, our results show that plasma leptin concentrations increase progressively with higher grades of hypertensive retinopathy even after correction for BMI, suggesting that a critical leptin level is needed for the development of retinopathy. Elevated concentrations of plasma leptin might be secondary to the release of leptin by the vascular endothelium damaged by high blood pressure, as an epiphenomenon. However, a pathogenic role for leptin in hypertensive retinopathy cannot be excluded.


   Acknowledgments
 
We thank Dr. Zeki Bayraktar for the assessment of hypertensive retinopathy. We are grateful to Atilla H. Elhan, Department of Biostatistics, Ankara University; and Dr. Mustafa Turan, Gulhane School of Medicine, for statistical help. We thank Dr. Erol Cerasi, Department of Endocrinology, Hadassah Medical Center, University of Jerusalem; and Dr. Julio Licinio, Clinical Neuroendocrinology Branch, NIH, for critical review of the manuscript.


   Footnotes
 
1 This work was supported by the Research Center of Gulhane School of Medicine. Back

Received February 12, 1999.

Revised October 5, 1999.

Accepted October 26, 1999.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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