Optogenetic modulation of intraocular pressure in a glucocorticoid-induced ocular hypertension mouse model

Tia J. Kowal, Philipp P. Prosseda, Ke Ning, Biao Wang, Jorge Alvarado, Brent E. Sendayen, Sayena Jabbehdari, W. Daniel Stamer, Yang Hu, Yang Sun

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Purpose: Steroid-induced glaucoma is a common form of secondary open angle glaucoma characterized by ocular hypertension (elevated intraocular pressure [IOP]) in response to prolonged glucocorticoid exposure. Elevated IOP occurs with increased outflowwresistance and altered trabecular meshwork (TM) function. Recently, we used an optogenetic approach in TM to regulate the 5-phosphatase, OCRL, which contributes to regulating PI(4,5)P2 levels. Here, we applied this system with the aim of reversing compromised outflow function in a steroid-induced ocular hypertension mouse model. Methods: Elevated IOP was induced by chronic subconjunctival dexamethasone injections in wild-type C57Bl/6j mice. AAV2 viruses containing optogenetic modules of cryptochrome 2 (Cry2)-OCRL-5ptase and CIBN-GFP were injected into the anterior chamber. Four weeks after viral expression and dexamethasone exposure, IOP was measured by tonometer and outflow facility was measured by perfusion apparatus. Human TM cells were treatedwith dexamethasone, stimulated by light and treated with rhodamine-phalloidin to analyze actin structure. Results: Dexamethasone treatment elevated IOP and decreased outflow facility in wildtype mice. Optogenetic constructs were expressed in the TM of mouse eyes. Light stimulation caused CRY2-OCRL-5ptase to translocate to plasma membrane (CIBN-CAAX-GFP) and cilia (CIBN-SSTR3-GFP) in TM cells, which rescued the IOP and outflow facility. In addition, aberrant actin structures formed by dexamethasone treatment were reduced by optogenetic stimulation in human TM cells in culture. Conclusions: Subcellular targeting of inositol phosphatases to remove PIP2 represents a promising strategy to reverse defective TM function in steroid-induced ocular hypertension. Translational Relevance: Targeted modulation of OCRL may be used to decrease steroid-induced elevated IOP.

Original languageEnglish (US)
Article number10
JournalTranslational Vision Science and Technology
Volume10
Issue number6
DOIs
StatePublished - 2021
Externally publishedYes

Keywords

  • Dexamethasone
  • Inositol phosphatase
  • Intraocular pressure
  • Primary cilia
  • Steroid-induced glaucoma

ASJC Scopus subject areas

  • Biomedical Engineering
  • Ophthalmology

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