The Inhibitory Effects of a Peripherally Restricted CB1 Receptor Antagonist on Myofibroblast Transdifferentiation of Human Retinal Pigment Epithelial Cells

TL;DR

A new drug called JD5037 can block the transformation of retinal cells into myofibroblasts, which may help treat retinal fibrosis.

Contribution

JD5037, a peripherally restricted CB1 antagonist, is shown for the first time to inhibit myofibroblast transdifferentiation in retinal pigment epithelial cells.

Findings

JD5037 significantly reduced TNT-induced collagen gel contraction in human RPE cells.

JD5037 attenuated the expression of α-SMA and fibronectin, markers of myofibroblasts.

CB1 receptor knockdown eliminated JD5037's inhibitory effects on myofibroblast transdifferentiation.

Abstract

What are the main findings?
JD5037 inhibits myofibroblast transdifferentiation of human retinal pigment epithelial cells.The effects of JD5037 involves CB1 cannabinoid receptor.

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.

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.

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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