抄録
Background: Trabecular meshwork remodeling leads to aqueous humor outflow resistance and increases intraocular pressure, one of the major risk factor of glaucoma. Renin angiotensin system (RAS) inhibitors are known to attenuate tissue remodeling in cardiovascular system, however their effects on human trabecular meshwork (HTM) are poorly understood.
Objectives: To evaluate dose and time-dependent effects of RAS inhibitors on production and degradation of ECM in dexamethasone-treated HTM cells.
Methods: HTM cells were divided into ten groups: Group 1 was cultured in medium only; group 2 in medium with dexamethasone 1E-7 M. The rest of the groups were co-treated with dexamethasone 1E-7 M and enalaprilat dehydrate or losartan potassium in concentrations of 1E-4, 1E-5, 1E-6, and 1E-7 M for both drugs. All groups were incubated for 7 and 14 days. Immunocytochemistry, western blot and ELISA were performed to measure fibronectin, a-smooth muscle actin (a-SMA), metalloproteinase (MMP) 2 and 9, and tissue inhibitors of MMPs (TIMPs) 1 and 2.
Results: Dexamethasone significantly increased production of fibronectin, a-SMA and both TIMP-1 and 2 by day 14 of treatment while significantly reducing production of MMP-2 and MMP-9. Both RAS inhibitors abolished the effects of dexamethasone on ECM deposition by decreasing production of fibronectin and a-SMA at all tested concentrations and both time points with the maximum reduction (p<0.05) 1.82 and 1.93 folds for fibronectin and 2.62 and 1.95 folds for a-SMA in enalaprilat and losartan treated groups, respectively. Compared to dexamethasone-treated group, MMP-2 and 9 levels showed significant increase by 3.08 and 3.78 folds in enalaprilat and by 2.93 and 4.10 folds in losartan co-treated groups, while both TIMP-1 and 2 levels were significantly reduced by 2.25 folds and 2.13 folds in enalaprilat-treated group and by 2.25 folds and 2.64 folds in losartan-treated group. No significant differences were found between all tested doses of both drugs.
Conclusion: RAS inhibitors significantly decrease ECM deposition in dexamethasone treated HTM cells which is likely contributed by modulating of production MMPs and TIMPs. Both groups, ACE inhibitors and ARBs, are potentially attractive in the treatment of glaucoma.
We acknowledge the financial support from the grants: 600-IRMI/MyRA 5/3BESTARI (013/2017).
