TXNDC5 in POAG: Promoting Extracellular Matrix Protein Accumulation and Raising Intraocular Pressure

Excessive accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) leads to increased resistance to outflow of aqueous humor (AH) and the consequent increase in intraocular pressure (IOP) in primary open-angle glaucoma (POAG). Currently, there is no effective treatment to address this pathogenic mechanism of POAG. Therefore it is essential to screen for key proteins that are involved in TM ECM accumulation and further develop drugs targeting these mechanisms.

Proteins were screened for significant up-regulation in TGFβ2-induced TM by label-free quantitative proteomics techniques. The relationship between TXNDC5 and ECM proteins was analyzed via qPCR, Western blot, and immunohistochemistry and validated in mice. Autophagy inhibitors (CQ) and protein synthesis inhibitors (CHX) were used, and molecular chaperone-mediated autophagy (CMA) activity was modulated to validate the degradation pathway-dependent mechanism of TXNDC5.

We confirmed that in human TM cells, TXNDC5 contributed to the accumulation of ECM by increasing the expression of TGFβ R2. We also demonstrated that TXNDC5 was degraded through the CMA pathway, and that the AR7 was able to reverse TGFβ2-induced TM ECM accumulation. Most importantly, in vivo experiments have demonstrated that knockdown of TXNDC5 significantly reduced TGFβ2-induced ECM protein accumulation in TM tissues and reduces TGFβ2-induced ocular hypertension in the mouse.

We revealed the role and probable mechanism by which TXNDC5 leads to TM ECM accumulation and IOP elevation, suggesting that targeting elevation of TXNDC5 is a potential new therapeutic approach to reduce TM ECM protein accumulation in POAG.