Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork

Kasetti, Ramesh Babu; Maddineni, Prabhavathi; Millar, J. A.; Clark, Abbot F.; Zode, Gulab

doi:10.1038/s41598-017-14938-0

Cited by 71 publications

(82 citation statements)

References 61 publications

(68 reference statements)

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“…40,41 In this study it was shown in a human lens 3D model for the first time a clear induction of EMT by glucocorticoid treatment at clinically relevant concentrations. The data are well in line with other studies in the eye showing induction of EMT by a-SMA of, for example, the trabecular mesh 42 and gives further evidence that there is a mechanistic link between PSC and PCO in humans. This might further explain why PCO is more frequent with patients who underwent cataract surgery after drug-induced PSC.…”

Section: Human 3d Lens Spheroid Model 61supporting

confidence: 91%

A Human Three-Dimensional In Vitro Model of Lens Epithelial Cells as a Model to Study Mechanisms of Drug-Induced Posterior Subcapsular Cataracts

Plüss

Kustermann

2020

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Cataract is a pathological opacification of the lens, which is still one of the leading causes of blindness in the world. Several etiologies are described, among them drug-induced cataract, for example, posterior subcapsular cataract (PSC) after steroid treatment. To investigate different mechanisms of drug-induced cataract a human three-dimensional (3D) lens in vitro model was developed, consisting of immortalized human lens epithelial cells. Methods: These cells were cultivated on 96-well, ultralow attachment plates, where they rapidly form spheroids. By gene expression analysis different markers were observed, which are important to maintain lens transparency, such as ephrin type-A receptor 2 (EphA2) or a-smooth muscle actin (a-SMA). Results: The lens epithelial cells form a spheroid within a few days and show stable expression of important lens marker, and size and viability remain stable up to 26 days in culture. The gene expression of the glucocorticoid-treated spheroids revealed a clear shift in the expression of EphA2, a-SMA, aB-crystallin (CRYAB), and heat shock protein beta-1 (HSPB1). Furthermore, the glucocorticoid treatment did not improve cell survival. Conclusions: This study proposes a useful 3D in vitro model, which expresses important lens markers and is capable of demonstrating features found in drug-induced cataracts. As the viability remains stable over long time, this model can also be used for long-term treatment. The main characteristics are the increased expression of a-SMA, CRYAB, and HSPB1 and the decreased expression of EphA2. The present data provide some first evidence on novel mechanisms involved in glucocorticoid-induced cataracts.

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Section: Human 3d Lens Spheroid Model 61supporting

confidence: 91%

A Human Three-Dimensional In Vitro Model of Lens Epithelial Cells as a Model to Study Mechanisms of Drug-Induced Posterior Subcapsular Cataracts

Plüss

Kustermann

2020

Journal of Ocular Pharmacology and Therapeutics

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“…Importantly, the IOP in two patients increased only during the administration of dexamethasone (10 mg/m 2 ) and not during the administration of prednisolone (60 mg/m 2 ). Dexamethasone increases the secretory protein load of extracellular matrix proteins in the endoplasmic reticulum (ER) of trabecular meshwork cells, thereby inducing chronic ER stress 10 and promoting ocular hypertension via the transforming growth factor 2 signaling. 11 In the current study, IOP of younger patients with ALL was higher than those who were > 10 years.…”

Section: Discussionmentioning

confidence: 99%

Corticosteroid‐induced glaucoma in pediatric patients with hematological malignancies

Sugiyama

Terashita

Hara

et al. 2019

Pediatric Blood & Cancer

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Background Corticosteroids, especially dexamethasone, play a critical role in chemotherapy for pediatric hematological malignancies. We previously observed that patients with complaints of headache or photophobia during corticosteroid administration had high intraocular pressure (IOP). Procedure We measured IOP during corticosteroid administration in 15 patients with acute leukemia or lymphoma undergoing treatment at our institution from January 2016 to December 2018. IOP was measured by an ophthalmologist within seven days of the initiation of standard dose of corticosteroid, which was defined as 60 mg/m2/day for prednisolone and 10 mg/m2/day for dexamethasone. Results Fifteen patients received 52 courses of chemotherapy containing corticosteroids. IOP exceeded 21 mmHg among 13 patients in 28 courses. Twelve of the 13 patients were administered topical treatment, and six of the 12 patients needed additional diuretic agents. IOP during the chemotherapy courses containing dexamethasone was significantly higher compared with IOP during the chemotherapy courses containing prednisolone. Only two patients complained of symptoms, such as headache and photophobia, and one of the two patients underwent trabeculotomy. Funduscopic findings were normal in all patients. There was a dose‐associated decrease in IOP with reduction of dexamethasone dose. Conclusions IOP should be measured during administration of substantial corticosteroid doses even in patients with no symptoms. Further investigations regarding the level of IOP for intervention need to be conducted.

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“…We recently demonstrated that Dex-induced intracellular fibronectin and type I collagen interact and co-localize with KDEL antibody, which recognizes the ER stress markers GRP78 and GRP94 (44). Here, we examined whether inhibition of TGF␤ signaling prevents Dex-induced co-localization of fibronectin and type I collagen with KDEL in primary human TM cells (Fig.…”

Section: Inhibition Of Tgf␤ Signaling Reduces Dex-induced Ecm Accumulmentioning

confidence: 99%

Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension

Kasetti

Maddineni

Patel

et al. 2018

Journal of Biological Chemistry

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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 β (TGFβ) signaling, leading to GC-induced ECM accumulation, ER stress, and IOP elevation. Dex increased both the precursor and bioactive forms of TGFβ2 in conditioned medium and activated TGFβ-induced SMAD signaling in primary human TM cells. Dex also activated TGFβ2 in the aqueous humor and TM of a mouse model of Dex-induced ocular hypertension. We further show that mice are protected from Dex-induced ocular hypertension, ER stress, and ECM accumulation. Moreover, treating WT mice with a selective TGFβ 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 TGFβ2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGFβ signaling. Our results indicate that TGFβ2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension.

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Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork

Cited by 71 publications

References 61 publications

A Human Three-Dimensional In Vitro Model of Lens Epithelial Cells as a Model to Study Mechanisms of Drug-Induced Posterior Subcapsular Cataracts

A Human Three-Dimensional In Vitro Model of Lens Epithelial Cells as a Model to Study Mechanisms of Drug-Induced Posterior Subcapsular Cataracts

Corticosteroid‐induced glaucoma in pediatric patients with hematological malignancies

Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension

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