| First Author | Kasetti RB | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 25 | Pages | 9854-9868 |
| PubMed ID | 29743238 | Mgi Jnum | J:274279 |
| Mgi Id | MGI:6196916 | Doi | 10.1074/jbc.RA118.002540 |
| Citation | Kasetti RB, et al. (2018) Transforming growth factor beta2 (TGFbeta2) signaling plays a key role in glucocorticoid-induced ocular hypertension. J Biol Chem 293(25):9854-9868 |
| abstractText | Elevation of intraocular pressure (IOP) is a serious adverse effect of glucocorticoid (GC) therapy. Increased extracellular matrix (ECM) accumulation and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) is associated with GC-induced IOP elevation. However, the molecular mechanisms by which GCs induce ECM accumulation and ER stress in the TM have not been determined. Here, we show that a potent GC, dexamethasone (Dex), activates transforming growth factor beta (TGFbeta) signaling, leading to GC-induced ECM accumulation, ER stress, and IOP elevation. Dex increased both the precursor and bioactive forms of TGFbeta2 in conditioned medium and activated TGFbeta-induced SMAD signaling in primary human TM cells. Dex also activated TGFbeta2 in the aqueous humor and TM of a mouse model of Dex-induced ocular hypertension. We further show that Smad3(-/-) mice are protected from Dex-induced ocular hypertension, ER stress, and ECM accumulation. Moreover, treating WT mice with a selective TGFbeta receptor kinase I inhibitor, LY364947, significantly decreased Dex-induced ocular hypertension. Of note, knockdown of the ER stress-induced activating transcription factor 4 (ATF4), or C/EBP homologous protein (CHOP), completely prevented Dex-induced TGFbeta2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGFbeta signaling. Our results indicate that TGFbeta2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension. |
