Abstract
Elevated intraocular pressure (IOP) is a major risk factor in developing primary open angle glaucoma (POAG), which is the most common form of glaucoma. Transforming growth factor-beta 2 (TGFβ2) is a pro-fibrotic cytokine that plays an important role in POAG pathogenesis. TGFβ2 induced extracellular matrix (ECM) production, deposition and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) contribute to increased aqueous humor (AH) outflow resistance and IOP elevation. Drugs which alter the glaucomatous fibrotic changes and ER stress in the TM may be effective in reducing ocular hypertension. Astragaloside IV (AS.IV), a novel saponin isolated from the roots of Astragalus membranaceus, has demonstrated antifibrotic and ER stress lowering effects in various tissues during disease conditions. However, the effect of AS.IV on glaucomatous TM fibrosis, ER stress and ocular hypertension has not been studied. Primary human TM cells treated with AS.IV decreased TGFβ2 induced ECM (FN, Col-I) deposition and ER stress (KDEL, ATF4 and CHOP). Moreover, AS.IV treatment reduced TGFβ2 induced NF-κB activation and αSMA expression in TM cells. We found that AS.IV treatment significantly increased levels of matrix metalloproteases (MMP9 and MMP2) and MMP2 enzymatic activity, indicating that the antifibrotic effects of AS.IV are mediated via inhibition of NF-κB and activation of MMPs. AS.IV treatment also reduced ER stress in TM3 cells stably expressing mutant myocilin. Interestingly, the topical ocular AS.IV eye drops (1 mM) significantly decreased TGFβ2 induced ocular hypertension in mice, and this was associated with a decrease in FN, Col-1 (ECM), KDEL (ER stress) and αSMA in mouse TM tissues. Taken together, the results suggest that AS.IV prevents TGFβ2 induced ocular hypertension by modulating ECM deposition and ER stress in the TM.
Highlights
Primary open angle glaucoma (POAG) is the most common type of glaucoma, accounting for nearly 74% of all glaucoma cases [1,2]
Apart from extracellular matrix (ECM) deposition, our studies have shown that endoplasmic reticulum (ER) stress plays a major role in glaucomatous trabecular meshwork (TM) dysfunction [10,11,12,13,14,15]
Current glaucoma therapeutics are effective in reducing intraocular pressure (IOP), but none address the underlying pathological mechanisms of TM dysfunction in POAG such as ECM accumulation and ER stress
Summary
Primary open angle glaucoma (POAG) is the most common type of glaucoma, accounting for nearly 74% of all glaucoma cases [1,2]. In POAG, there is increased resistance to aqueous humor outflow through the TM, leading to an elevation of IOP [4,5]. Increased synthesis and deposition of extracellular matrix (ECM) proteins in the TM (TM fibrosis) are responsible for TM dysfunction and the subsequent increase in AH outflow resistance [6,7,8,9]. Chronic ER stress disturbs ER homeostasis affecting the processing and secretion of ECM proteins, leading to abnormal ECM accumulation in the TM [9]. Increased synthesis of ECM proteins overloads the ER processing capacity, which leads to induction of ER stress and to abnormal ECM accumulation in the TM [15]. Current glaucoma therapeutics are effective in reducing IOP, but none address the underlying pathological mechanisms of TM dysfunction in POAG such as ECM accumulation and ER stress. Targeting ECM accumulation and ER stress in the TM may provide a novel treatment that mitigate disease progression in the treatment of glaucoma
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