Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma.

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.

• Authors: Ramesh B Kasetti, Prabhavathi Maddineni, Bindu Kodati, Bhavani Nagarajan, Sam Yacoub
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 22 (Nov 19 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34830390 (Publication Type: Journal Article)

Chemical References

• Saponins
• Tgfb2 protein, mouse
• Transforming Growth Factor beta2
• Triterpenes
• astragaloside A

Topics

• Animals
• Aqueous Humor (drug effects)
• Disease Models, Animal
• Glaucoma, Open-Angle (drug therapy, genetics, pathology)
• Humans
• Intraocular Pressure (drug effects)
• Mice
• Ocular Hypertension (drug therapy, genetics, pathology)
• Saponins (pharmacology)
• Trabecular Meshwork (drug effects, pathology)
• Transforming Growth Factor beta2 (genetics)
• Triterpenes (pharmacology)