Role of Glucocorticoids and Glucocorticoid Receptors in Glaucoma Pathogenesis

Abstract

The glucocorticoid receptor (GR), including both alternative spliced isoforms (GRα and GRβ), has been implicated in the development of primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG). POAG is the most common form of glaucoma, which is the leading cause of irreversible vision loss and blindness in the world. Glucocorticoids (GCs) are commonly used therapeutically for ocular and numerous other diseases/conditions. One serious side effect of prolonged GC therapy is the development of iatrogenic secondary ocular hypertension (OHT) and OAG (i.e., GC-induced glaucoma (GIG)) that clinically and pathologically mimics POAG. GC-induced OHT is caused by pathogenic damage to the trabecular meshwork (TM), a tissue involved in regulating aqueous humor outflow and intraocular pressure. TM cells derived from POAG eyes (GTM cells) have a lower expression of GRβ, a dominant negative regulator of GC activity, compared to TM cells from age-matched control eyes. Therefore, GTM cells have a greater pathogenic response to GCs. Almost all POAG patients develop GC-OHT when treated with GCs, in contrast to a GC responder rate of 40% in the normal population. An increased expression of GRβ can block GC-induced pathogenic changes in TM cells and reverse GC-OHT in mice. The endogenous expression of GRβ in the TM may relate to differences in the development of GC-OHT in the normal population. A number of studies have suggested increased levels of endogenous cortisol in POAG patients as well as differences in cortisol metabolism, suggesting that GCs may be involved in the development of POAG. Additional studies are warranted to better understand the molecular mechanisms involved in POAG and GIG in order to develop new disease-modifying therapies to better treat these two sight threatening forms of glaucoma. The purpose of this timely review is to highlight the pathological and clinical features of GC-OHT and GIG, mechanisms responsible for GC responsiveness, potential therapeutic options, as well as to compare the similar features of GIG with POAG.

Stress, Allostatic Load, and Neuroinflammation: Implications for Racial and Socioeconomic Health Disparities in Glaucoma

“…One proposed pathway involved in glial cell dysfunction and neuroinflammation is the interaction between glial cells and glucocorticoids. Although glucocorticoids are often used as potent anti-inflammatory agents, there is evidence that even an endogenous exposure to glucocorticoids may be implicated in glaucoma development [14].…”

“…A recent review by Patel et al explored the possible pathophysiologic mechanisms in GIG. The prevailing theory is that glucocorticoids induce multifactorial damage to the trabecular meshwork that inhibits the drainage of the aqueous humor and causes an increased IOP [14]. There are two glucocorticoid receptor (GR) variants, known as GRα and GRβ.…”

“…There are two glucocorticoid receptor (GR) variants, known as GRα and GRβ. The role of GRβ has been implicated in downregulating the activity of GRα and blunting the response to glucocorticoids [14]. In eyes isolated from patients with primary open-angle glaucoma (POAG), decreased GRβ activity was observed, suggesting that there is a heightened glucocorticoid responsiveness in POAG patients [20].…”

“…In eyes isolated from patients with primary open-angle glaucoma (POAG), decreased GRβ activity was observed, suggesting that there is a heightened glucocorticoid responsiveness in POAG patients [20]. Additionally, about 40% of the general population exhibited an increased IOP in response to exogenous steroids, compared to nearly 100% of POAG patients [14,21,22]. There is also evidence that individuals who demonstrate an increased IOP when exposed to exogenous steroids may be at an increased risk for POAG in the future [14].…”

“…Additionally, about 40% of the general population exhibited an increased IOP in response to exogenous steroids, compared to nearly 100% of POAG patients [14,21,22]. There is also evidence that individuals who demonstrate an increased IOP when exposed to exogenous steroids may be at an increased risk for POAG in the future [14]. Although the mechanism for this is not completely understood, in a review of steroid-induced glaucoma (SIG), Roberti et al, hypothesized that genetic variations that lead to a differing expression of GRα and GRβ may play a role in different response phenotypes [23].…”