Molecular Vision 2025; 31:245-254 <http://www.molvis.org/molvis/v31/245>
Received 02 February 2025 | Accepted 12 September 2025 | Published 14 September 2025

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Cysteinyl leukotriene receptor 1 regulates cellular glucose levels in human retinal cells

Andreas Koller, Susanne Maria Brunner, Julia Preishuber-Pflügl, Daniela Mayr, Christian Runge, Herbert Anton Reitsamer, Andrea Trost

Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University, Salzburg, Austria

Correspondence to: Andreas Koller Department of Ophthalmology and Optometry University Hospital of the Paracelsus Medical University Muellner Hauptstrasse 48 5020 Salzburg Austria; Phone: +43 (0)5 7255 24237; email: a.koller@salk.at

Abstract

Purpose: Cysteinyl leukotriene receptor 1 (CysLTR1), originally described as a proinflammatory G protein-coupled receptor, has been shown to possess diverse nonimmunological properties. One of these functions is to modulate glucose-stimulated insulin secretion in β cells. Furthermore, the inhibition of CysLTR1 increases retinal cell survival in early diabetic retinopathy. Nevertheless, the potential of CysLTR1 to modulate glucose levels in retinal vascular cells, such as endothelial cells (ECs) and pericytes (PCs), is unknown. Therefore, we determined the intracellular glucose levels in retinal cells in vitro after the inhibition of CysLTR1 under standard and high-glucose culture conditions.

Methods: Primary human ECs, PCs, and the ARPE-19 cell line were cultured under standard (5.5 mmol/l glucose + 27.5 mmol/l mannitol) and high-glucose (33.0 mmol/l) conditions in the absence and presence of the specific CysLTR1 antagonists montelukast and zafirlukast for 1, 3, and 7 days. CysLTR1 expression was determined by immunofluorescence microscopy. CysLT secretion was measured by enzyme-linked immunosorbent assay. The effects of high glucose and CysLTR1 inhibition on cell viability and intracellular glucose levels were analyzed by luminescence-based assays. Furthermore, the transendothelial and transepithelial electrical resistance of the ECs and ARPE-19 monolayers was measured.

Results: CysLTR1 inhibition under standard glucose culture conditions increased the cellular glucose levels in retinal ECs, PCs, and ARPE-19 cells after 1 and 3 days of treatment. Under high-glucose culture conditions, CysLTR1 inhibition for 1 day reduced the intracellular glucose level in ARPE-19 cells. However, CysLTR1 inhibition for 3 days increased the level of intracellular glucose in ARPE-19 cells under high-glucose culture conditions. Furthermore, CysLTR1 inhibition reduced the tightness of the EC and ARPE-19 monolayers under standard culture conditions but increased the tightness of the ARPE-19 monolayers under high-glucose conditions.

Conclusions: CysLTR1 is considered a potential target for the treatment of type 2 diabetes and early diabetic retinopathy. Our data revealed that CysLTR1 activity directly regulates cellular glucose levels in retinal cells, supporting these hypotheses. Interestingly, the effect of CysLTR1 activity on glucose levels was reversed under acute metabolic stress. Thus, the activity of CysLTR1 appears to be more complex in terms of glucose metabolism and needs to be studied in more detail.

Introduction

Cysteinyl leukotrienes (CysLTs) were first described in the late 1970s as proinflammatory lipid mediators [1]. The three different CysLTs, LTC4, LTD4, and LTE4, are derived from the arachidonic acid pathway and act via three known G protein-coupled receptors, CysLT receptor 1 (CysLTR1), CysLT receptor 2, and 2-oxoglutarate receptor 1 (also designated CysLTE) [2,3]. However, in addition to their proinflammatory activity, CysLTs and their receptors have been shown to regulate diverse noninflammatory processes and cell systems, such as angiogenesis, cell stress, and the endosomal-lysosomal axis [4-9]. Similarly, CysLT receptors are expressed in diverse cell types, including immune, endothelial, epithelial, and neuronal cells [3,10]. Similarly, we observed strong CysLTR1 and CysLTR2 receptor expression in human and rodent retinas in different tissue layers [11]. In a previous study, the role of CysLTR1 in the basal functions of the retina was investigated, and we revealed that CysLTR1 regulates the presence of immune cells, capillary diameter, and proteasome activity in the retinas of aged mice [12]. However, the regulatory mechanism leading to these observed effects is still unknown. Therefore, further studies are needed to clarify the specific role of CysLTR1 in retinal tissues. Recently, the inhibition of CysLTR1 by specific antagonists, such as montelukast (MK) and zafirlukast (ZK), as well as CysLTR1 knockdown, has been shown to increase glucose-stimulated insulin secretion in β cells [13,14], leading to a decrease in blood glucose levels in mice [14]. The authors of these studies highlighted the potential of CysLTR1 antagonists in the treatment of type 2 diabetes [13,14]. Additionally, high glucose levels lead to an increase in LTC4 synthesis in retinal endothelial cells (ECs) [15]. Interestingly, CysLTR1 inhibition by MK prevented early retinopathy in a streptozotocin-induced diabetic mouse model, leading to neuronal survival and a reduction in acellular capillaries [16]. The beneficial effects of CysLTR1 inhibition in diabetic retinopathy are attributed to the modulation of inflammatory processes, oxidative stress, and retinal angiogenesis [16,17]. Retinal ECs and pericytes (PCs), which are part of the blood-retinal barrier, play a key role in tissue supply and lead to functional disabilities under hyperglycemic conditions [18]. Therefore, it is of great interest to understand how ECs and PCs respond to different blood glucose levels under physiologic and pathophysiologic conditions. To our knowledge, the regulatory effect of CysLTR1 activity on the intracellular glucose levels of retinal cells, such as ECs and PCs, has not yet been investigated. Therefore, the aim of the present study was to determine the effects of CysLTR1 inhibition on intracellular glucose levels and transendothelial and transepithelial electrical resistance (TEER) in human primary retinal ECs and retinal PCs, as well as in the human retinal pigment epithelial cell line ARPE-19 under standard and high-glucose conditions.

Methods

Primary cells, cell line, and treatment

Primary retinal ECs were obtained from Cell Biologics (Chicago, IL; H-6065, 2x male) and Zen-Bio (Durham, NC; HRE-F-ZB, 1x female). Primary retinal PCs were obtained from PELOBiotech (Planegg, Germany, PB-CH-061–2211, 2x male) and Zen-Bio (HRP-F-ZB, 1x female). ECs and PCs were cultured as recommended by the suppliers. All dishes used for different experiments were coated with a gelatin-based coating solution (6950; Cell Biologics), as described by the manufacturer. Specific EC (H1168; Cell Biologics) and PC (PB-MH-031–4000; PELOBiotech) growth media were used to culture primary cells. ARPE-19 cells were obtained from ATCC (VA) and cultured in RPMI/F-12 medium (Thermo Fisher Scientific, Waltham, MA) containing 10% fetal bovine serum (Thermo Fisher Scientific). Treatments were performed using medium with standard glucose (5.5 mmol/l [1 g/l]) and high-glucose (33 mmol/l [6 g/l]; Merck, Darmstadt, Germany). To avoid osmotic differences between standard and high-glucose media, 5 g/l (27.5 mmol/l) mannitol (Merck) was added to standard glucose medium. The cells were treated with vehicle (0.01% DMSO), 100 nM or 1,000 nM MK (Selleck Chemicals, Houston, TX), or 100 nM or 1,000 nM ZK (Selleck Chemicals) for 1 day, 3 days, and 7 days in standard glucose or high-glucose media. The medium containing the specific CysLTR1 antagonists was replaced every second day.

Immunofluorescence staining analysis

Primary retinal ECs and PCs were cultured in gelatin-based coated chamber slides. Afterward, the cells were washed with phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde for 20 min. After being washed with PBS, the cells were incubated in 50 mM tris-buffered saline (TBS) + 0.5% Triton X-100 + 1% bovine serum albumin (BSA; Merck) + 5% donkey serum for 1 h at room temperature (RT). The cells were subsequently washed with TBS (50 mM) and incubated in 50 mM TBS + 0.5% Triton X-100 + 1% BSA containing a specific antibody against CysLTR1 (1:100, AB151484–1001; Abcam, Cambridge, UK) overnight at RT. The next day, the buffer was aspirated, and the cells were washed with TBS. The cells were incubated for 1 h with 50 mM TBS + 0.5% Triton X 100 + 1% BSA containing Alexa 555–tagged donkey sera (1:1,000, Thermo Fisher Scientific) and 4′,6-diamidino-2-phenylindole (1:4,000) to visualize the primary antibody and the cell nuclei, respectively. The cells were subsequently washed with TBS and embedded in TBS-glycerol (1:1). Secondary antibody-only controls were used to identify nonspecific binding sites.

Documentation

A confocal laser-scanning unit (AxioObserver Z1 attached to an LSM710, Zeiss, Oberkochen, Germany; 20× dry or 63× oil immersion objective lenses, numerical aperture 1.30, Zeiss) was used to document fluorescence. Single optical section mode was used for image acquisition with appropriate filter settings for 4′,6-diamidino-2-phenylindole (345 nm excitation) and Alexa Fluor 555 (509 nm excitation).

Luminescence assays

ECs, PCs, and ARPE-19 cells were seeded (5,000 cells/well) in white 96-well plates with clear bottoms. The next day, the cells were treated for 1 day, 3 days, or 7 days. All treatments were performed in duplicate. The number of viable cells was determined with a CellTiter-Glo Luminescent Cell Viability Kit according to the manufacturer’s instructions (G7570; Promega, Madison, WI). Intracellular glucose was measured with a Glucose-Glo Assay (J6021; Promega) following the manufacturer’s instructions.

Enzyme-linked immunosorbent assay

To measure apical and basal CysLT secretion, EC cells (20,000 cells/well) were cultured with standard and high-glucose media in gelatin-coated 12-well Transwell inserts (0.4 µm pore size; Corning Inc., Corning, NY) for 7 days. PCs (20,000 cells/well) were cultured with standard and high-glucose media in gelatin-coated 24-well plates for 3 days. Twenty-four hours after the last medium exchange, the supernatants, including the basal and apical supernatants of the ECs, were collected. CysLTs were measured with a specific enzyme-linked immunosorbent assay according to the manufacturer’s instructions (ADI-900–070; Enzo Biochem Inc., Farmingdale, NY).

TEER measurement

Primary retinal ECs and ARPE-19 cells were seeded at high confluence (20,000 cells/well) and allowed to rest for 1 day in the gelatin-coated 12-well Transwell inserts before treatment. Cells were cultured with standard and high-glucose media containing the specific treatment components in Transwell inserts for 7 days. The total ohmic resistance was measured with an EVOM and Endohm-12 (World Precision Instruments, Sarasota, FL). PBS was used as the apical and basolateral media for the measurements. The net resistance was calculated by subtracting the blank resistance from the total ohmic resistance. The TEER (Ohm × cm2) was calculated by multiplying the net resistance by the culture area (1.1 cm2).

Statistical analysis

All the statistical analyses were performed with GraphPad Prism 10.1.2 (GraphPad Software, La Jolla, CA, USA). The applied statistical tests are specified in each figure legend. A p value of <0.05 was considered statistically significant.

Results

Primary ECs (n = 3) and PCs (n = 3) were obtained from six independent male and female donors. First, we analyzed CysLTR1 expression in the primary retinal ECs and PCs by immunofluorescence analysis. ECs and PCs from all donors presented positive CysLTR1 protein expression, and the secondary antibody controls did not result in an immunofluorescence signal (Figure 1A-C). Additionally, both cell types secreted CysLTs, ranging from approximately 40 to 550 pg/ml, in the supernatant (Figure 1D). High glucose increased basal CysLT secretion from ECs of individual donors by 64 to 347 pg/ml (D1), 100 to 115 pg/ml (D2), and 40 to 142 pg/ml (D3; Figure 1D). However, high glucose levels had no effect on apical CysLT secretion from ECs and CysLT secretion from PCs (Figure 1D).

To provide evidence of the damaging effect of high glucose on retinal cells in our cell culture model, we analyzed the effect of high glucose levels on the number of viable cells by a luminescence-based assay. Although similar numbers of cells were seeded, the cells from different donors exhibited clear differences in cell growth, leading to high interexperimental variations and high differences in the relative luminescence unit values of the controls. Therefore, the values were normalized to those of the experimental control. High glucose in the medium significantly affected the relative number of viable cells after 1 day (main effect: p < 0.0001) and 7 days (main effect: p = 0.0240) of treatment; however, this effect was not observed on day 3 (Figure 2A). Treatment with CysLTR1 antagonists had no effect on the number of viable cells analyzed after 1 day, 3 days, or 7 days of treatment (Appendix 1). Afterward, we examined the effect of high glucose levels in the medium on glucose uptake. Therefore, the intracellular glucose levels were measured by a luminescence-based assay. The presence of high glucose levels in the medium led to significantly increased (approximately 7.5- to 15-fold) intracellular glucose levels in ECs and PCs on day 1 (main effect: p = 0.0019) and day 3 (main effect: p = 0.0055) of cultivation (Figure 2B) compared with those in cultures with standard glucose levels. The relative glucose uptake on day 7 tended to increase (approximately fivefold) in cells exposed to high glucose in the medium (Figure 2B) compared to cells exposed to medium containing standard glucose.

Interestingly, the treatment of retinal ECs and PCs cultured under standard glucose conditions with two CysLTR1 antagonists, MK and ZK, at two different concentrations, 100 nM and 1000 nM, led to an overall increase in the intracellular glucose levels after 1 day (main effect: p = 0.0425) and 3 days (main effect: p = 0.0383) of treatment. Multiple comparison analyses revealed that 1,000 nM ZK had a significant effect on the glucose uptake of retinal ECs and PCs after 1 day (p = 0.0303) and 3 days (p = 0.0124) of treatment. Treatment with 1,000 nM MK tended to increase intracellular glucose levels in retinal cells (Figure 3A) after 1 and 3 days of treatment. After 7 days of treatment with MK or ZK, retinal ECs and PCs no longer presented elevated intracellular glucose levels compared to those of the vehicle controls (Figure 3A). Under high-glucose conditions, CysLT1 inhibition had no significant effect on intracellular glucose levels in retinal ECs and PCs as antagonist treatment resulted in either an increase or a decrease in intracellular glucose levels in individual donors (Figure 3B).

To confirm the effect of CysLTR1 inhibition on intracellular glucose levels in retinal ECs and PCs, we antagonized CysLTR1 in retinal pigment epithelial (RPE) cells. Therefore, we treated the RPE cell line ARPE-19 with CysLTR1 inhibitors for 1 day and 3 days under standard and high-glucose conditions. Like primary cells, ARPE-19 cells exhibited increased glucose uptake after CysLTR1 inhibition (main effect: p = 0.0013; Figure 4A). Similarly, 1,000 nM ZK had the strongest effect on glucose uptake (p = 0.0010), but 100 nM ZK and 1,000 nM MK also significantly increased the intracellular glucose levels in ARPE-19 cells (p = 0.0100 and p = 0.0018, respectively; Figure 4A). However, under high-glucose conditions, treatment with 1,000 nM ZK for 1 day significantly decreased (p = 0.0071) the glucose uptake of cells, and 100 nM ZK tended to reduce the intracellular glucose levels (Figure 4B). MK treatment for 1 day had no significant effect on intracellular glucose levels under high-glucose culture conditions (Figure 4B). Interestingly, the glucose uptake of ARPE-19 cells cultured for 3 days under high-glucose conditions was significantly increased (p = 0.0163) in the presence of 1,000 nM ZK, whereas a lower dose of ZK and MK had no significant effect on the intracellular glucose levels (Figure 4B).

High glucose levels affect the tightness and tight junction proteins of retinal endothelial monolayers, leading to a reduction in TEER [19,20]. Therefore, we analyzed the TEER of retinal ECs and ARPE-19 cells after CysLTR1 inhibition. The cells were cultured in the presence of standard and high glucose and CysLTR1 inhibitors for 7 days. High glucose levels significantly reduced the TEER in primary retinal ECs (p = 0.0049) and ARPE-19 cells (p = 0.0014; Figure 5). Interestingly, under standard glucose conditions, treatment with 100 nM ZK significantly reduced (p = 0.0446) the TEER, and 1,000 nM ZK tended to decrease the TEER (Figure 5A). Neither MK nor ZK affected the TEER of ECs cultured under high-glucose conditions (Figure 5A). In ARPE-19 cells, 100 nM MK (p = 0.0346) and 1,000 nM ZK (p = 0.0029) significantly reduced the TEER in the presence of standard glucose levels (Figure 5B). However, in the presence of 1,000 nM MK (p = 0.0346), 100 nM ZK (p = 0.0131) or 1,000 nM ZK (p = 0.0048), and high glucose levels, ARPE-19 monolayers presented a significant increase in the TEER compared to that of cells without CysLTR1 inhibition (Figure 5B). Interestingly, the inhibition of CysLTR1 with 1,000 nM ZK had the opposite effect (p = 0.0008) on the TEER, which was dependent on the glucose level in the medium.

Discussion

CysLTs and their receptors have been shown to be important in controlling retinal vascular permeability and angiogenesis [4] and play a role in retinal pathologies, such as diabetic retinopathy or ocular hypertension [17,21]. Additionally, we demonstrated high expression of leukotriene system components in healthy human and rodent retinas, identifying CysLTR1 expression in diverse retinal cell types, which suggests the importance of CysLT signaling under physiologic conditions [11]. Although we were able to identify the participation of CysLTR1 in immunoaging, capillary aging, and proteostasis in vivo and in vitro [7,9,12], the specific basal functions of CysLTR1 in the retina are still unclear. Thus, further investigations are necessary to identify the role of the CysLT system in retinal cells.

In the present study, we showed that both human retinal ECs and PCs clearly expressed CysLTR1 and secreted CysLTs, suggesting autocrine and paracrine cell stimulation under basal conditions in vitro. These data suggest a physiologic role for CysLTs and their receptors in retinal ECs and PCs. Retinal ECs had already been demonstrated to secrete CysLTs, as measured by mass spectrometry, and this secretion was further increased by high glucose levels [15]. Similarly, we observed an increase in basal CysLT secretion from ECs of individual donors.

High glucose levels severely affect ECs and PCs by impairing cell metabolism and cell proliferation and increasing oxidative stress, which can lead to cell senescence or cell death [22-25]. Similarly, we observed a small reduction in viable cells under high-glucose culture conditions after 1 day and 7 days of treatment. The mechanism by which high glucose led to a decrease in viable cells was not examined in this study.

In the present study, CysLTR1 inhibition increased and decreased the intracellular glucose levels depending on the cell type and culture conditions. Under basal culture conditions, CysLTR1 inhibition increased glucose uptake in retinal ECs, PCs, and ARPE-19 cells. Thus, CysLTR1 functions to restrict intracellular glucose levels and may be important for maintaining cellular homeostasis in retinal cells of the inner and outer blood-retinal barrier [26,27]. Decreased glucose uptake after CysLTR1 inhibition was observed only under acute high-glucose conditions but not after 3 days in ARPE-19 cells. Hence, cultured cells seem to react to high glucose, as shown by altered CysLTR1 activity. After 3 days of high-glucose treatment, CysLTR1 activity was similar to that observed under standard glucose conditions, resulting in increased intracellular glucose levels upon CysLTR1 inhibition. This potentially suggests an adaptation of cells to high-glucose conditions [28]. Interestingly, CysLTR1 inhibition in primary ECs and PCs in the presence of high glucose led to a decrease or an increase in intracellular glucose levels, depending on the donor and treatment duration. Thus, intraindividual differences seem to affect the response of retinal cells to high glucose levels.

As high glucose was shown to reduce the TEER in EC and RPE monolayers [19,20], the increased intracellular glucose levels induced by high glucose or CysLTR1 inhibition under standard glucose could lead to the reduced tightness of retinal ECs and ARPE-19 monolayers observed in this study. Interestingly, in the presence of high glucose, CysLTR1 inhibition prevented the loss of monolayer tightness in ARPE-19 cells. Similarly, high glucose levels seemed to change CysLTR1 activity in ARPE-19 cells. The reason why high glucose levels reduce the monolayer integrity may be multifactorial and cell type dependent. In ECs, the reduced monolayer tightness was not due to changes in tight junction protein expression [19]. However, EC barrier function has been shown to be reduced by increased posttranslational glycation of the tight junction protein occludin induced by carbonyl stress after exposure to high glucose [29]. Interestingly, high glucose affected tight junction expression in ARPE-19 cells, but this modulation did not affect monolayer barrier function [30]. In addition, high glucose has been shown to increase the migratory capacity of RPE cells induced by oxidative stress [31], which may explain the reduced barrier function in ARPE-19 cells. The exact mechanism by which high glucose disrupts the barrier function of the RPE monolayer remains unclear and much debated [32]. Whether the regulation of intracellular glucose levels via CysLTR1 affects EC and epithelial monolayer tightness should be addressed in more detail in future studies.

A duality of CysLTR1 action has also been observed in the modulation of autophagic activity in ARPE-19 cells; on the one hand, CysLTR1 inhibition induced autophagy when basal activity was inactive, and on the other hand, it inhibited autophagy when basal activity was high [6]. Interestingly, in comparison with MK, ZK exhibited greater potential to modulate the intracellular glucose levels. Similarly, we observed a greater potential of ZK to modulate the autophagic process [6]. Intracellular glucose affects autophagic capacity, and whether the CysLTR1-dependent regulation of glucose uptake and autophagy modulation are connected should be addressed in future studies. Furthermore, the mechanism by which CysLTR1 regulates glucose uptake remains unknown and should be addressed in future studies.

In summary, this study demonstrated that retinal ECs and PCs expressed CysLTR1 and secreted CysLTs. CysLTR1 restricted glucose uptake under basal conditions in retinal ECs, PCs, and ARPE-19 cells and increased glucose uptake under acute high-glucose conditions in ARPE-19 cells. Therefore, CysLTR1 inhibition increased (ECs, PCs, and ARPE-19 cells) and reduced (ARPE-19 cells) glucose uptake under basal and acute high-glucose conditions, respectively. Additionally, CysLTR1 inhibition reduced the tightness of retinal ECs and ARPE-19 monolayers under basal culture conditions but prevented the high glucose-dependent loss of monolayer tightness in ARPE-19 cells. The specific antagonist ZK exhibited greater potential to modify intracellular glucose levels and monolayer tightness compared to that of MK. The capacity of CysLTR1 to regulate intracellular glucose levels supports previous suggestions for targeting CysLTR1 activity in the treatment of type 2 diabetes and diabetic retinopathy. However, the duality of CysLTR1 in modulating glucose uptake under basal and metabolic cell stress conditions requires a more detailed analysis to understand its potential to modulate hyperglycemia-dependent pathologies.

Appendix 1. Supplementary Figure 1.

Acknowledgments

This study was supported by 2022-SEED-023-Brunner. Competing interests The authors declare that they have no competing financial or nonfinancial interests. Availability of data and materials The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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