Anti-fibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis

Elife. 2021 Mar 30:10:e60831. doi: 10.7554/eLife.60831.

Abstract

Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.

Keywords: contractility; fibrosis; glaucoma medications; human; medicine; mouse; steroid glaucoma; trabecular meshwork.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Benzoates / pharmacology*
  • Female
  • Humans
  • Infant, Newborn
  • Intraocular Pressure / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Ocular Hypertension / drug therapy*
  • Prospective Studies
  • Tonometry, Ocular
  • beta-Alanine / analogs & derivatives*
  • beta-Alanine / pharmacology
  • rho-Associated Kinases / antagonists & inhibitors*

Substances

  • Antihypertensive Agents
  • Benzoates
  • beta-Alanine
  • rho-Associated Kinases
  • netarsudil