TY - JOUR
T1 - Transforming growth factor 2 (TGF2) signaling plays a key role in glucocorticoid-induced ocular hypertension
AU - Kasetti, Ramesh B.
AU - Maddineni, Prabhavathi
AU - Patel, Pinkal D.
AU - Searby, Charles
AU - Sheffield, Val C.
AU - Zode, Gulab S.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants EY022077, EY026177, and EY024259 from the NEI and by funding from the North Texas Eye Research Institute in Fort Worth, TX. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Dr. Abbot Clark, Sherri Harris, and Sandra Maansson for sharing mice, animal colony maintenance, and paraffin sectioning, respectively. We also thank Dr. John Hulleman for providing critical feedback on this manuscript.
Funding Information:
This work was supported by National Institutes of Health Grants EY022077, EY026177, and EY024259 from the NEI and by funding from the North Texas Eye Research Institute in Fort Worth, TX. The authors declare that they have no conflicts of interest with the contents of this article. The con-tent is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018 Kasetti et al.
PY - 2018/6/22
Y1 - 2018/6/22
N2 - 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 (TGF) signaling, leading to GC-induced ECM accumulation, ER stress, and IOP elevation. Dex increased both the precursor and bioactive forms of TGF2 in conditioned medium and activated TGF-induced SMAD signaling in primary human TM cells. Dex also activated TGF2 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 TGF 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 TGF2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGF signaling. Our results indicate that TGF2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension.
AB - 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 (TGF) signaling, leading to GC-induced ECM accumulation, ER stress, and IOP elevation. Dex increased both the precursor and bioactive forms of TGF2 in conditioned medium and activated TGF-induced SMAD signaling in primary human TM cells. Dex also activated TGF2 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 TGF 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 TGF2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGF signaling. Our results indicate that TGF2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension.
UR - http://www.scopus.com/inward/record.url?scp=85048950684&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.002540
DO - 10.1074/jbc.RA118.002540
M3 - Article
C2 - 29743238
AN - SCOPUS:85048950684
SN - 0021-9258
VL - 293
SP - 9854
EP - 9868
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -