Abstract
Glaucoma is a major cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP), which causes optic nerve damage and retinal ganglion cell death, is the primary risk factor for blindness in glaucoma patients. IOP is controlled by the balance between aqueous humor secretion from the ciliary body (CB) and its drainage through the trabecular meshwork (TM). How microRNAs (miRs) regulate IOP and glaucoma in vivo is largely unknown. Here we show that miR-143 and miR-145 expression is enriched in the smooth muscle and trabecular meshwork in the eye. Targeted deletion of miR-143/145 in mice results in significantly reduced IOP, consistent with an ~2-fold increase in outflow facilities. However, aqueous humor production in the same mice appears to be normal based on a microbeads-induced glaucoma model. Mechanistically, we found that miR-143/145 regulates actin dynamics and the contractility of TM cells, consistent with its regulation of actin-related protein complex (ARPC) subunit 2, 3, and 5, as well as myosin light chain kinase (MLCK) in these cells. Our data establish miR-143/145 as important regulators of IOP, which may have important therapeutic implications in glaucoma.
Highlights
Glaucoma is the leading cause of irreversible vision loss, affecting ~70 million people worldwide[1]
Several studies have established the involvement of miRNAs in glaucoma. miR-29 family genes have been shown to regulate the expression of multiple extracellular matrix (ECM) components in trabecular meshwork (TM) cells11–13. miR-24 regulates the induction of TGFβ1 in TM cells in response to cyclic mechanical stress14. miR-200c inhibits the contraction and reduces traction force in TM cells, and miR-200c mimic has been shown to decrease intraocular pressure (IOP) by ~25% in rats[15]
Human TM (HTM) cells were isolated from donor eyes with no history of eye disease, and the expression of miR-143 and miR-145 was examined by qRT-PCR. miR-143/145 expression in HTM cells appeared to be less but comparable to the expression in human aortic smooth muscle cells (HASMC), but more abundant than in human umbilical vein endothelial cells (HUVEC) (Fig. 1A,B)
Summary
Glaucoma is the leading cause of irreversible vision loss, affecting ~70 million people worldwide[1]. Drugs that target TM contraction or relaxation, including sphingosine-1-phosphate 2 (S1P2) receptor antagonists that block myosin light chain (MLC) phosphorylation, and Rho kinase or LIM-kinase 2 inhibitors, have been shown to relax TM cells, increase outflow facilities, and lower IOP6–9. Inhibition of miR-200c using an adenoviral vector expressing a molecular sponge to miR-200c led to a significant increase in IOP These results establish the potential of modulating trabecular contraction and IOP by miRNA in vivo. Our results demonstrate that miR-143/145 regulates IOP and outflow facilities in vivo, suggesting that manipulating miR-143/145 level may have therapeutic implications in glaucoma
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