Enhanced Circulating Soluble LR11 in Patients With Diabetic Retinopathy

doi:10.1016/j.ajo.2012.01.035

American Journal of Ophthalmology

Volume 154, Issue 1, July 2012, Pages 187-192

https://doi.org/10.1016/j.ajo.2012.01.035 Get rights and content

Purpose

To investigate the relationship of circulating levels of soluble form of LR11 (sLR11; also called SorLA or SORL1), with the progression of proliferative diabetic retinopathy (PDR) in patients with type 2 diabetes mellitus.

Design

Cross-sectional study.

Methods

Fifty-four patients with type 2 diabetes mellitus were divided into 2 sex- and age-matched groups: one with PDR (n = 29) and the other with nonproliferative diabetic retinopathy (n = 25). The serum sLR11 levels were measured with an immunodetection system followed by chemifluorescence quantification.

Results

The serum sLR11 levels were higher in the PDR group than in the nonproliferative diabetic retinopathy group (5.8 ± 1.2 U vs 3.7 ± 1.3 U; P < .01). A multivariate regression analysis showed that circulating sLR11 is a factor contributing to the prediction of PDR independent of other classical risk factors, and an area under the receiver operating characteristic curve analysis revealed that the sensitivity and the specificity were equivalent to or more than those of other factors. Among the classical risk factors for PDR, glycosylated hemoglobin levels showed the highest correlation coefficient (P < .01) for the sLR11 concentrations.

Conclusions

Serum sLR11 concentration may reflect the progression of PDR in patients with type 2 diabetes mellitus. sLR11, released from immature vascular cells and indicating the development of atherosclerosis, is expected to be a novel candidate biomarker indicating diabetic retinopathy in patients with type 2 diabetes mellitus.

Section snippets

Study Population

The subjects consisted of 56 consecutive Japanese patients with type 2 diabetes mellitus seeking treatment at the Department of Laboratory Vascular Function, Toho University Sakura Medical Center, who had already given blood samples. PDR was defined according to the international clinical classification of diabetic retinopathy as neovascularization in the retina.¹² Vitreous surgeries had been performed to treat macular edema (n = 7), vitreous hemorrhage (n = 13), traction retinal detachment (n

Results

The patient characteristics are shown in Table 1. The age- and gender-matched NPDR and PDR groups comprised 25 and 29 subjects, respectively. There were no statistically significant differences in BMI, duration of diabetes, frequency of hyperlipidemia or dyslipidemia, or estimated glomerular flow rate between the NPDR and PDR subjects. There were also no statistically significant differences in HbA1c, fasting blood sugar, or lipid concentrations between the NPDR and PDR subjects. Although there

Discussion

LR11 is highly expressed in the endothelial cells under the condition of dyslipidemia as well as in the intimal smooth muscle cells migrated from media in the development of atherosclerosis.2, 3 Two recent independent studies for the subjects with dyslipidemia or coronary heart diseases have shown that the concentrations of soluble form, sLR11, were associated with the HbA1c levels in these subjects with different backgrounds.4, 5

The key cytokines underlying the pathogenesis and development of

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Cited by (15)

Circulating soluble LR11, a differentiation regulator for vascular cells, is increased during pregnancy and exaggerated in patients with pre-eclampsia
2019, Clinica Chimica Acta
Citation Excerpt :
In order to delineate the involvement of vascular cell differentiation in the complex systemic inflammatory conditions in pre-eclampsia, the current study focuses on the role of a differentiation regulator for vascular cells, sLR11. The rationale for the study lies in the observation that circulating sLR11 levels are indicative of the pathological chronic inflammatory cellular conditions in atherosclerotic patients with cardiovascular diseases [14–19] and obese patients with type 2 diabetes [17,20–22], known as chronic inflammatory diseases in the vascular wall [10,23]. LR11 was originally identified in vascular intimal de-differentiated SMCs, which display highly activated migration and cytokine release [30].
Pre-eclampsia is a pregnancy-specific disease characterized by onset of hypertension and proteinuria, sometimes progressing into damaging other organs. Here, we investigated the pathological significance of the soluble fragment of LR11 (sLR11), a cell differentiation regulator, in comparison to circulating IL-6 and TNF-α, in pre-eclampsia.
The study was conducted in a cross-sectional research design with fourteen pre-eclampsia patients and fifty healthy pregnant subjects. Pre-eclampsia was defined as hypertensive disorders in pregnancy at over 20 weeks of gestation with proteinuria.
Plasma levels of sLR11 as well as IL-6 in pre-eclampsia were increased compared with those in the healthy pregnant subjects at the first, the second, and the third trimester. Receiver operating characteristic analysis for the detection of pre-eclampsia among third-trimester subjects showed that the areas under the curves of sLR11 and IL-6 were equivalent. sLR11 and IL-6 correlated positively with TNF-α in healthy pregnant subjects. In the pre-eclampsia patients, there was neither a correlation between sLR11 and IL-6 nor between sLR11 and TNF-α.
sLR11 increases during pregnancy, with levels further exaggerated in pre-eclampsia, and may be related to the pathology of pre-eclampsia.
Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss
2016, Atherosclerosis
Citation Excerpt :
In HepG2 and smooth muscle cell cultures, LR11 expression and sLR11 release are stimulated by triglyceride-rich lipoproteins (TGRL) [18], which are typically increased in subjects with T2D [19,20]. Compared to healthy controls, levels of sLR11 are higher in individuals with T2D [21,22] and are correlated with hemoglobin A1c (HbA1c) levels [21,23,24]. Individuals with T2D, complicated by coronary stenosis, acute coronary syndrome, or retinopathy, display increased plasma sLR11 levels, suggesting a link with the severity of vascular complications in these patients [21,23,25].
Cardiovascular disease (CVD) is a major complication in patients with type 2 diabetes (T2D), especially in those with obesity. Plasma soluble low density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of atherosclerosis and has been linked to the metabolism of triglyceride-rich lipoproteins, adiposity, and vascular complications in T2D. We aimed to determine the effect of diet-induced weight loss on plasma sLR11 levels in overweight and obese individuals with T2D.
Plasma sLR11 levels were determined in 64 individuals with T2D and BMI >27 kg/m² before and after a 20-week weight loss diet. As a reference, sLR11 levels were also determined in 64 healthy, non-obese controls, matched as a group for age and sex.
Median plasma sLR11 levels of the T2D study-group at baseline (15.4 ng/mL (IQR 12.9–19.5)) were higher than in controls (10.2 (IQR: 8.7–12.2) ng/mL; p = 0.001). The diet resulted in a weight loss of 9.7 ± 5.2% (p = 0.001) and improved CVD risk factors. sLR11 levels were reduced to 13.3 ng/mL (IQR 11.0–17.1; p = 0.001). Changes in sLR11 levels positively associated with changes in non-HDL cholesterol (B = 1.54, R² = 0.17, p = 0.001) and HbA1c (B = 0.07, R² = 0.11, p = 0.007), but not with weight loss (B = 0.04, R² = 0.05, p = 0.076). The changes in non-HDL cholesterol and HbA1c together explained 24% of the variance of sLR11 reduction (p = 0.001).
Weight loss dieting in overweight and obese individuals with T2D resulted in a reduction in plasma sLR11 levels that was associated with improvements in lipid-profile and glycemic state.
Circulating soluble form of LR11, a regulator of smooth muscle cell migration, is a novel marker for intima-media thickness of carotid arteries in type 2 diabetes
2016, Clinica Chimica Acta
Citation Excerpt :
We have developed a sandwich enzyme-linked immunosorbent assay (ELISA) for the exact quantitation of circulating sLR11 using specific monoclonal antibodies against human LR11 [12,13]. With this method, it could be shown that the concentrations of sLR11 were increased in patients with familial hypercholesterolemia [14], coronary artery diseases [15–17], type 2 diabetes (T2D) [15,18,19], and in patients with hematological malignancies [13,20–23]. Notably, several independent studies have shown that the concentrations of sLR11 were increased in relation to markers of glycemic disturbances among the classical risk factors for atherosclerosis [11,14–16,18,19].
Smooth muscle cell (SMC) migration from the media to the intima, a process affecting plaque stability in advanced-stage atherosclerosis, is under the control of LR11. To delineate the clinical significance of the circulating soluble form of LR11 (sLR11) in patients with type 2 diabetes (T2D), we analyzed the correlation of sLR11 levels with intima-media thickness (IMT) of carotid arteries.
Plasma sLR11 levels were measured in 165 patients with T2D (mean age 56.2 ± 10.4 y, 58.2% males, and BMI 24.6 ± 3.6) by ELISA. Averaged IMT levels of common carotid arteries were determined by ultrasonography.
Circulating sLR11 levels were 9.8 ± 3.5 ng/ml, and correlated positively with the classical atherosclerosis risk factors age, sex, systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C), fasting plasma-glucose (FPG), and glycosylated hemoglobin. Multivariate linear regression analysis indicated that only FPG was associated with sLR11; sLR11 correlated positively with IMT, together with age and FPG, but less with LDL-C. Among the serum risk factors for IMT, multivariate linear regression analysis uncovered that sLR11 was independently associated with IMT. Subsequent logistic analysis revealed that FPG correlated best with IMT values at a cut-off of 0.80 mm and sLR11 at a cut-off of 0.90 mm, respectively, while LDL-C showed lower discriminatory power at any IMT cut-off values.
Increased sLR11 concentrations are highly associated with increased IMT as well as with FPG in middle-aged, non-obese patients with T2D. Circulating sLR11 may be a novel marker representing the pathophysiology of intimal SMCs in patients with T2D.
Circulating LR11 is a novel soluble-receptor marker for early-stage clinical conditions in patients with non-hodgkin's lymphoma
2014, Clinica Chimica Acta
Citation Excerpt :
LDL receptor relative with 11 ligand-binding repeats (LR11; also known as SorLA or SORL1) is a type I membrane protein that plays a key role in the migration of undifferentiated vascular smooth muscle cells via uPAR upregulation [16–18]. Serum sLR11 is a biomarker for arteriosclerosis [19], acute coronary syndrome [20], and diabetic retinopathy [21]. Moreover, increased sLR11 concentrations in the cerebrospinal fluid are a prospective marker of Alzheimer disease [22].
We reported that the soluble LDL receptor relative with 11 ligand-binding repeats (sLR11) is a promising biomarker for follicular lymphoma (FL). In this study, we evaluated the fluctuations in serum sLR11 levels compared with those of serum soluble urokinase-type plasminogen activator receptor (suPAR) and soluble interleukin-2 receptor (sIL-2R) in patients with non-Hodgkin's lymphoma (NHL).
Serum sLR11, suPAR, and sIL-2R levels were measured using ELISA in 175 NHL patients and 57 healthy controls. The levels at diagnosis and at remission were evaluated in 64 paired samples.
Serum sLR11 levels were significantly increased in FL, diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma patients compared with healthy controls. Serum sLR11 levels revealed significant positive correlations with serum suPAR and sIL-2R levels. Serum sLR11 levels at remission were decreased compared with those at diagnosis, and the declines at remission expressed a slope of approximately − 1 with an intercept near that of controls. The receiver operating characteristic–area under the curve of serum sLR11 concentrations was equivalent to that of serum suPAR and sIL-2R concentrations in an early-stage DLBCL and FL.
sLR11 may be a novel soluble receptor indicative of early-stage NHL, with potential use for evaluating therapeutic efficacy.
SORLA Expression in Synaptic Plexiform Layers of Mouse Retina
2020, Molecular Neurobiology
Association of sLR11 gene polymorphism with T2DM and carotid atherosclerosis
2018, Technology and Health Care

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Original articleEnhanced Circulating Soluble LR11 in Patients With Diabetic Retinopathy

Purpose

Design

Methods

Results

Conclusions

Section snippets

Study Population

Results

Discussion

Atherosclerosis

Ann Thorax Surg

Ann Thorax Surg

Ophthalmology

Exp Eye Res

Int J Biochem Cell Biol

Diabetes Res Clin Pract

The pathobiology of diabetic complications: a unifying mechanism

Diabetes

Modulation of smooth muscle cell migration by members of the low-density lipoprotein receptor family

Arterioscler Thromb Vasc Biol

Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha

Circ Res

AngII-stimulated migration of vascular SMC is dependent on LR11

J Clin Invest

Original article
Enhanced Circulating Soluble LR11 in Patients With Diabetic Retinopathy