The Inhibitory Effects of a Peripherally Restricted CB1 Receptor Antagonist on Myofibroblast Transdifferentiation of Human Retinal Pigment Epithelial Cells
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA
Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40292, USA
Eye Hospital of China Academy of Chinese Medical Sciences, Beijing 100040, China
Department of Ophthalmology and Visual Sciences, Ohio State University College of Medicine, Columbus, OH 43210, USA
Abstract
Highlights
What are the main findings?
- JD5037 inhibits myofibroblast transdifferentiation of human retinal pigment epithelial cells.
- The effects of JD5037 involves CB1 cannabinoid receptor.
What are the implications of the main findings?
- CB1 cannabinoid receptor may be a therapeutic target for retinal fibrosis.
- Peripherally restricted CB1 antagonists such as JD5037 have potential in preventing and treating fibrotic retinal conditions.
Abstract
Myofibroblasts derived from retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of retinal fibrotic conditions such as proliferative vitreoretinopathy (PVR). Upon exposure to growth factors and cytokines such as TNF-α and TGF-β (TNT), RPE cells undergo epithelial-mesenchymal transition and subsequent transdifferentiation to contractile myofibroblasts. In this study, the effects of JD5037, a peripherally restricted CB1 antagonist, on myofibroblast transdifferentiation of primary cultures of human RPE cells were assessed. JD5037 significantly reduced TNT-induced, RPE cell-mediated collagen gel contraction, an indicator of myofibroblast function, in a concentration-dependent manner. Western blot analysis showed that JD5037 attenuated TNT-induced expression of α-SMA and fibronectin, two molecular markers of myofibroblasts. Furthermore, siRNA knockdown of CB1 cannabinoid receptor partially inhibited TNT-induced myofibroblast transdifferentation of human RPE cells and eliminated the inhibitory effects of JD5037 on myofibroblast transdifferentiation. These data demonstrate, for the first time, that peripherally restricted antagonists, such as JD5037, targeting the CB1 cannabinoid receptor have therapeutic potential for PVR and other retinal fibrotic conditions.
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Keywords: retinal pigment epithelial cells, CB1 cannabinoid receptor, myofibroblast
Article notes
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Received 2025 Dec 25; Revised 2026 Feb 10; Accepted 2026 Feb 26; Collection date 2026 Mar.
1. Introduction
Proliferative vitreoretinopathy (PVR) usually arises as a complication of retinal detachment and leads to failure of retinal detachment surgery in approximately 5–10% of cases [1]. PVR is a potentially blinding disorder characterized by the formation of a contractile epiretinal membrane (ERM) that can lead to retinal folds or tractional detachments [1,2,3]. Among the various cell types present in ERMs, retinal pigment epithelium (RPE) cells are one of the main retinal cells considered to contribute to the pathophysiology of PVR [4,5]. During PVR development, RPE cells are dispersed into the vitreous cavity and are subretinally exposed to the growth factor and cytokines [4,5]. Under the influence of cytokines such as TNF-α and TGF-β, RPE cells undergo an epithelial to mesenchymal transition, and then transdifferentiate into myofibroblasts, gaining the ability to migrate, proliferate, and secrete fibrotic extracellular matrices (ECMs) [4,5,6]. Thus, myofibroblast transdifferentiation from RPE cells significantly contributes to the formation of the ERM found in PVR. Furthermore, transdifferentiated myofibroblasts are contractile, causing the ERM to pull on the vitreous and/or retina, causing retinal detachments [4,5,6]. To date, PVR can only be treated with surgical intervention, including vitrectomy and/or epiretinal membrane (ERM) peel, and, currently, no approved pharmaceutical intervention for PVR exists [1,2,3]. Drugs that are proven to prevent RPE transdifferentiation into myofibroblasts would be valuable to potentially treat or prevent PVR.
The endocannabinoid system (ECS) is composed of cannabinoid receptors, including CB1 and CB2, endogenous cannabinoid ligands such as anandamide (N-arachidonoyl ethanolamide) and 2-arachidonoyl glycerol (2-AG), as well as the enzymes responsible for the synthesis and degradation of these endogenous cannabinoids [7,8,9]. Previous research has shown that CB1 receptors are present in human RPE cells [10,11]. In addition, it has been shown that the CB1 receptor is upregulated in primary cultured human RPE cells that have undergone oxidative stress, and inhibiting the CB1 receptor helps prevent oxidative stress-induced RPE cell death [11].
In recent years, cannabinoids have gained wide interest for their therapeutic value. For example, CB1 antagonists like rimonabant initially worked effectively for controlling obesity and certain metabolic conditions [12]. However, it was later revealed that rimonabant, which readily crosses the blood–brain barrier, exhibited unwanted psychiatric side effects in patients [13,14]. Therefore, interest has now turned to peripherally restricted CB1 antagonists, such as JD5037, to avoid the side-effects of CB1 antagonism in the central nervous system [13,14].
Previous studies have shown that the CB1 receptor is involved in the pathogenesis of liver fibrosis [15]. For example, CB1 receptors were upregulated in liver samples from patients and mouse models with liver fibrosis [16]. Activation of CB1 receptors promoted activation of hepatic stellate cells (HSCs), while blockage of CB1 receptors with JD5037, a peripherally restricted CB1 antagonist, attenuated CB1 receptor-regulated HSC activation and liver fibrosis [16].
Based on the fact that CB1 receptors are expressed on the RPE cells and peripherally restricted CB1 antagonist JD5037 can inhibit liver fibrosis, in this study, we hypothesized that JD5037, by acting on CB1 receptor, may inhibit myofibroblast transdifferentiation of human RPE cells, a key step for the development of retinal fibrosis such as PVR.
2. Materials and Methods
2.1. Materials
JD5037 (catalogue number T4453) was purchased from Targetmol Chemicals Inc. (Wellesley Hills, MA, USA) and dissolved in ethanol to a concentration of 10 mM stock solution. TNF-α and TGF-β2 (catalogue numbers 300-01A-50UG and 100-35B-50UG, respectively) were purchased from Thermo Fisher Scientific (Waltham, MA, USA). Fetal bovine serum (FBS) (catalogue number F4135) was purchased from Sigma-Aldrich (St. Louis, MO, USA). Dulbecco’s modified Eagle’s medium (DMEM) (catalogue number 10-013-CV) was purchased from VWR (Radnor, PA, USA). Anti-α-SMA primary antibody (catalogue number 19245), and anti-mouse (catalogue number 7076) and anti-rabbit (catalogue number 7074) secondary antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA). Anti-CB1 (catalogue number sc-518035) and Anti-GAPDH (catalogue number sc-25778) primary antibodies were purchased from Santa Cruz Biotechnology (Dallas, TX, USA). Silencer Select siRNA for human CB1 (CNR1) (AM51331) and Silencer negative control siRNA (catalogue number 4390843) were purchased from Thermo Fisher Scientific (Waltham, MA, USA).
2.2. Primary Human RPE Cell Culture
Adult human primary RPE cells were procured from The Eye-Bank for Sight Restoration (New York, NY, USA). The eye bank is certified by Eye Bank Association of America (EBAA) to recover and provide human postmortem tissues for research. The establishment and characterization of these adult human RPE cells have been published in previous publications [6,17]. The cells were cultured in Matrigel coated flask, in Dulbecco’s modified Eagle’s medium (DMEM; VWR; Radnor, PA, USA), supplemented with 10% FBS (Sigma-Aldrich, St. Louis, MO, USA), 100 IU/mL penicillin, 100 μg/mL streptomycin, and 10 μM of ROCK inhibitor Y27632 (HelloBio, Princeton, NJ, USA). These adult human RPE cells were routinely passaged using trypsin and were used for contraction assays and western blot analysis at passages 3 or 4.
2.3. Contraction Assays
Primary cultured human RPE cells (passage 3 or 4) were plated on 0.4 mL of solidified neutralized type I collagen (Cellmatrix Type I-A, Fujifilm Wako Chemicals, Richmond, VA, USA) in each well of 24-well plates. RPE cells in 2.5% fetal bovine serum and DMEM were added to each well at 1 × 105 cells per well and incubated for 4 h to allow cell attachment. Cells were then pretreated with various concentrations of JD5037 for 15 min and subsequently treated with TGF-β2 + TNF-α (TNT; 10 ng/mL of each). Following 72 h of incubation, collagen gels were gently released from the wells and photographed after 4 h. Images were assessed for gel contraction and quantified using NIH ImageJ Software Version 1.54p. Results are mean ± SEM from three to four different experiments with different batches of cells. This well-established assay was used to measure the contraction of collagen matrix caused by the contraction of myofibroblasts, which were derived from RPE cells that were stimulated by cytokines [18,19].
2.4. Western Blot Analysis
Collagen gels with attached human RPE cells from the contraction assays were prepared for Western blot analysis using the lysis buffer (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM β-glycerophosphate, 1 mM Na3VO4, and 1 μg/mL leupeptin). After sonication and centrifugation to remove collagen, samples were reduced with DTT (0.1 M) in 4× loading buffer at 90 °C before being centrifuged at 12,000 rpm for 1 min. Proteins were then separated on a 10% SDS–polyacrylamide gel using a minigel electrophoresis system (Invitrogen, Waltham, MA, USA) and transferred to a nitrocellulose membrane. The membranes were blocked with 5% nonfat dried milk in TBS-T buffer (10 mM Tris-HCl, pH 8.0, 150 mM NaCl, and 0.3% Tween 20) and incubated overnight at 4 °C with primary antibodies anti-α-SMA, anti-CB1, and anti-GAPDH. After three 5-min washes with TBS-T, the membranes were incubated with a secondary antibody for 2 h at room temperature. The membranes were then washed three times with TBS-T for 5 min each, and protein bands were visualized using chemiluminescence substrates (Thermo Fisher Scientific, Waltham, MA, USA) and quantified using NIH ImageJ. Results are expressed as mean ± SEM from three to four independent experiments, normalized to the control.
2.5. Immunocytochemistry
RPE cells plated on collagen were first fixed with 4% paraformaldehyde, then washed, permeabilized, and blocked with 5% serum/0.3% Triton X-100/5% BSA in PBS. Next, the samples were incubated with an anti-α-SMA antibody labeled with Alexa Fluor 488 (Thermo Fisher Scientific, Waltham, MA, USA), and phalloidin labeled with CF583 (Biotium, Inc, Fremont, CA, USA) (to stain F actin stress fibers), in 1% BSA-PBS overnight at 4° C. After incubation, the samples were washed three times in 0.1% Triton X-100/PBS. Finally, the samples were mounted with Vectashield (Vector Laboratories, Burlingame, CA, USA) and were imaged under a fluorescence microscope with a digital camera.
2.6. siRNA Knockdown
Human RPE cells were transfected with CB1-specific siRNA (30 nM) or negative control siRNA using Lipofectamine 3000 reagent. Briefly, 30 μL of lipofectamine 3000 reagent was incubated with 30 μL of siRNA stock solution (10 μM) for 5 min in 1 mL of OptiMEM medium at room temperature. Subsequently. The siRNA/lipofectamine/Opti-MEM solution was added to RPE cells (grown to 80% confluency in a 10 cm cell culture plate) with 9 mL of fresh RPE cell culture medium described above (in Section 2.2) and incubated for 72 h. Specific knockdown of CB1 was confirmed by Western blot analysis. The siRNA experiments were conducted three times.
2.7. Statistical Analysis
Statistical analyses were performed using GraphPad Prism Version 10 (GraphPad Software, San Diego, CA, USA), with p-values < 0.05 considered statistically significant. One-way ANOVA or Student’s t test was used to assess differences in collagen matrix contraction assays or Western blot analyses among treatment groups.
3. Results
3.1. The Effects of JD5037 on Transdifferentiated RPE Cell-Mediated Collagen Matrix Contraction
Collagen matrix contraction assays were utilized to assess a key myofibroblast function, matrix contraction. In this assay, contraction is induced upon RPE cell transdifferentiation to myofibroblasts. As seen in Figure 1, treatment of human RPE cells with a combination of TGF-β2 and TNF-α (TNT, 10 ng/mL each) for 72 h resulted in significant collagen matrix contraction (Figure 1A). JD5037, which was developed to be a peripherally restricted ligand while maintaining the CB1 antagonistic activity, inhibited collagen matrix contraction in a concentration-dependent manner (Figure 1A,B). These data confirmed that combined treatment of TNT induces myofibroblast transdifferentiation of human RPE cells and demonstrated that JD5037 has an inhibitory effect on this process.
3.2. The Effects of JD5037 on Expression of Myofibroblast Markers α-SMA and Fibronectin in Transdifferentiated RPE Cells
Western Blot analysis was used to examine the expression of myofibroblast markers α-SMA and fibronectin in human RPE cells following contraction assays. As shown in Figure 2, expression levels of α-SMA and fibronectin were significantly enhanced by treatment with TNT (10 mg/mL). In addition, the levels of α-SMA and fibronectin were significantly reduced by treatment with JD5037 (3 μM) (Figure 2). These results are consistent with the results of the collagen matrix contraction assays, indicating that TNT-induced myofibroblast transdifferentiation of RPE cells was inhibited by JD5037.
3.3. The Effects of JD5037 on α-SMA Expression in F-Actin Stress Fibers of Transdifferentiated Human RPE Cells
As shown in Figure 3, immunofluorescent staining experiments revealed that TNT treatment induced the formation of F-actin stress fibers (red) in transdifferentiated RPE cells, and α-SMA (green) is incorporated into these stress fibers (orange/yellow in the merged image). In RPE cells treated with 3μM of JD5037, the expression of α-SMA (green) is reduced, and incorporation of α-SMA into F-actin stress fibers (orange/yellow in the merged image) is down-regulated compared to vehicle-treated cells (Figure 3). These data further demonstrated the inhibitory effects of JD5037 on the myofibroblast markers.
3.4. CB1 Expression in Human RPE Cells and Knockdown of CB1 by siRNA
Figure 4A shows western blot analysis of the expression of the CB1 cannabinoid receptor in human RPE cells. CB1 expression levels were significantly higher in the group treated with TNT (10 ng/mL each) than in the group treated with vehicle. Figure 4B shows that when compared to negative control siRNA treatment, transfection of human RPE cells with CB1-specific siRNA significantly knocked down CB1 expression in RPE cells. These results confirmed the presence of CB1 receptors in human RPE cells and demonstrated the successful knockdown of CB1 by specific siRNA against CB1.
3.5. The Impacts of CB1 Knockdown on TNT-Induced, RPE Cell-Mediated Collagen Matrix Contraction and the Inhibitory Effects of JD5037
Human RPE cells were transfected with CB1 siRNA to further elucidate the role of the CB1 receptor in the effects of JD5037 human RPE cells’ transdifferentiation. As shown in Figure 5, in RPE cells transfected with the negative control siRNA, TNT treatment induced a significant contraction of the collagen matrix (area of collagen matrix: 44.13 ± 4.39% of no TNT wells) that was significantly inhibited by the addition of JD5037 (area of collagen matrix: 70.90 ± 3.03% of no TNT wells). Upon transfection with the siRNA against CB1, however, TNT-induced collagen matrix contraction was significantly suppressed (area of collagen matrix: 67.66 ± 5.53% of no TNT wells), and addition of JD5037 did not have any significant effect on collagen matrix contraction (area of collagen matrix: 68.14 ± 4.45% of no TNT wells). These data further demonstrated that the CB1 cannabinoid receptor plays an important role in TNT-induced collagen matrix contraction, and JD5037 exerts its influence on collagen matrix contraction through the CB1 receptor on human RPE cells.
3.6. The Impacts of CB1 Knockdown on the Expression of Myofibroblast Markers α-SMA and Fibronectin in Human Transdifferentiated RPE Cells
Western Blot analysis was used to examine the expression of myofibroblast markers α-SMA and fibronectin in the transdifferentiated human RPE cells transfected with either the negative control siRNA or the CB1-specific siRNA following contraction assays. As seen in Figure 6, in cells transfected with negative control siRNA, treatment with TNT (10 ng/mL) led to a 4-fold enhancement of expression of α-SMA, which was suppressed by treatment with JD5037 (3 μM). In contrast, in cells transfected with CB1-specific siRNA, TNT-stimulated α-SMA expression was significantly dampened compared to control siRNA-treated cells and was not significantly different from no TNT control cells. Further addition of JD5037 treatment did not affect aSMA and fibronectin expression in cells transfected with CB1-specific siRNA. These data further confirm that the CB1 receptor is important for TNT-induced enhancement of α-SMA, and JD5037 exerts its effect to downregulate TNT-induced expression of α-SMA in human RPE cells via the CB1 receptor. These results are consistent with the results of the contraction assays, indicating that the CB1 cannabinoid receptor plays an important role in myofibroblast transdifferentiation of RPE cells, and the inhibitory effects of JD5037 on myofibroblast transdifferentiation are mediated by the CB1 receptor.
4. Discussion
The endocannabinoid system is emerging as a key modulator of fibrotic responses. For example, CB1 receptor activation has been observed to promote fibrosis in the liver, whereas CB1 inhibition has been shown to reverse or prevent these processes [15,16]. Another example, CB1 antagonist AM251 has been shown to inhibit skin fibroblast differentiation, a process involved in skin fibrosis [20]. The role of CB1 in relation to ocular fibrosis, however, is currently unknown. In the current study, we tested the hypothesis that the CB1 receptor is involved in the transdifferentiation of human RPE cells into myofibroblasts, a key process in the pathogenesis of PVR [4,5,6].
Previous work has reported that RPE cells exposed to proinflammatory and profibrotic cytokines contribute to the formation of epiretinal membranes, a hallmark of PVR [4,5,6,17,21]. Notably, both TGF-β and TNF-α are elevated in the vitreous of patients with PVR, and previous studies have demonstrated that combined treatment with TGF-β and TNF-α (TNT) induced transdifferentiation of human RPE cells into myofibroblasts, supporting the validity of this in vitro model for studying retinal fibrosis, specifically PVR [2,6].
Using this in vitro PVR model, in the current study, we found that JD5037, a peripherally restricted CB1 antagonist, concentration-dependently attenuated TNT-induced, RPE cell-mediated collagen contraction. In addition, JD5037 suppressed TNT-induced expression of myofibroblast markers a-SMA and fibronectin. Taken together, our data demonstrate the inhibition of transdifferentiation of RPE cells into myofibroblasts by JD5037.
Interestingly, the expression level of CB1 was upregulated upon treatment with a combination of TGF-β and TNF-α (TNT) that induced transdifferentiation of RPE cells into myofibroblasts. These data are consistent with previous findings in liver fibrotic models, where CB1 level was also significantly increased [14,16]. This finding suggests that CB1 signaling may be involved during fibrotic remodeling of the RPE cells.
To further study the involvement of CB1 receptor in myofibroblast transdifferentiation as well as the actions of JD5037, we demonstrated that knockdown of CB1 expression on RPE cells by the specific siRNA against CB1 mimicked the inhibitory effect of JD5037 on myofibroblast transdifferentiation, as evidenced by suppression of both TNT-induced collagen matrix contraction and TNT-induced enhancement of α-SMA and fibronectin expression. In addition, CB1 knockdown in RPE cells effectively negated any additional inhibitory effects of JD5037 on collagen matrix contraction as well as on TNT-induced expression of α-SMA and fibronectin. Together, these data support the notion that CB1 plays an important role in TNT-induced myofibroblast transdifferentiation of RPE cells and also confirm that the inhibitory effects of JD5037 on myofibroblast transdifferentiation of RPE cells are via the CB1.
The results from the current study are consistent with previous findings in hepatic fibrosis models, where JD5037 effectively reduced fibrogenesis [14,16]. The ability of JD5037 to exhibit similar anti-fibrotic effects in both liver and RPE cell models points to a broader, conserved role of CB1 signaling in regulating the fibrotic process. In addition, the involvement of CB1 in the fibrotic process has been shown previously with AM251, an older, not peripherally restricted CB1 antagonist, in skin fibroblasts [20]. The novelty of the current study, however, is that it demonstrates, for the first time, that the peripherally restricted CB1 antagonist can inhibit myofibroblast transdifferentiation of human RPE cells.
Importantly, JD5037 is a peripherally restricted CB1 antagonist that does not cross the blood–brain barrier, avoiding the neuropsychiatric side effects associated with earlier CB1 antagonists such as rimonabant [13,14,16]. This pharmacological property makes JD5037 a compelling candidate for repurposing in the prevention/treatment of fibrotic eye diseases such as PVR. A potential route of JD5037 administration is intravitreal, which would need to be tested in animal models of PVR in the future [22,23].
5. Conclusions
In summary, our findings demonstrated, for the first time, that JD5037, a peripherally restricted CB1 receptor antagonist, inhibits myofibroblast transdifferentiation of human RPE cells. Also, siRNA knockdown studies confirmed the involvement of the CB1 cannabinoid receptor in both the myofibroblast transdifferentiation of RPE cells and the inhibitory effects of JD5037. The data from this study point to the therapeutic potential of a peripherally restricted CB1 antagonist, such as JD5037, in preventing and treating fibrotic retinal conditions such as PVR. Further studies are warranted to elucidate the detailed downstream molecular mechanisms by which JD5037 exerts its actions and whether this compound inhibits pathogenic retinal fibrosis in vivo.
Abbreviations
The following abbreviations are used in this manuscript:
| RPE | Retinal pigment epithelial |
| PVR | Proliferative Vitreoretinopathy |
| ERM | Epiretinal membrane |
| TNT | TGF-β and TNF-α |
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cells15050418/s1, Figures S1 and S2: Original Western blot images.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author(s).
Conflicts of Interest
The authors declare no conflicts of interest.
Funding Statement
This research was funded in part by the National Institute of Health grant 1R21EY034634-01A1, and Research to Prevent Blindness (RPB) New Chair Challenge Grant to Sayoko Moroi (OSU Ophthalmology).
Footnotes
Footnote Group
References
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Associated Data
Supplementary Materials
Data Availability Statement
The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author(s).