Abstract
Purpose :
To determine the role of GDF-15, a divergent member of the transforming growth factor beta superfamily in trabecular meshwork physiology and homeostasis of intraocular pressure (IOP).
Methods :
Telomerase inhibitor, lipopolysaccharide (LPS), and tunicamycin were used to determine whether cellular senescence, inflammation, and ER (endoplasmic reticulum) stress, respectively, influence the expression of GDF-15 in human trabecular meshwork (TM) cells, utilizing ELISA and immunoblot analyses. To determine the role of GDF-15 in regulation of IOP, mildly anesthetized human GDF-15 overexpressing transgenic mice (C57BL/6J) and GDF-15 null mice (C57BL/6J) were monitored for changes in IOP using a rebound tonometer.
Results :
Treatment with telomerase inhibitor (20 µm BIBR1532, 24 hrs) and Tunicamyacin (one µg/ml for 48 hrs) but not LPS (1-5 µg/ml for 24 hrs) significantly increased GDF-15 levels in human TM cells. Transgenic mice expressing human GDF-15 exhibited significantly elevated human GDF-15 levels in both serum and aqueous humor compared to age-matched control mice. GDF-15 transgenic mice also exhibited a significant increase in IOP (~24 % P<0.01; n=16) compared to control mice. On the other hand, the GDF-15 null mice (n=15) maintained normal IOP.
Conclusions :
The increase in GDF-15 levels under senescence and ER stress and elevated IOP in GDF-15 overexpressing transgenic mice, when considered together with the known effects of GDF-15 on TM contractile/cell adhesive characteristics and elevated levels of GDF-15 in the aqueous humor of glaucoma patients, suggests that dysregulation of GDF-15 levels may be linked to ocular hypertension and glaucoma.
This is a 2021 ARVO Annual Meeting abstract.