Influence of Growth Differentiation Factor-15 on Intraocular Pressure in Mice

Growth differentiation factor-15 (GDF15), a stress sensitive cytokine, and a distant member of the TGF-beta superfamily, has been shown to exhibit increased levels with aging, and in various age-related pathologies. Although GDF15 levels are elevated in the aqueous humor (AH) of glaucoma (optic nerve atrophy) patients, the possible role of this cytokine in modulation of intraocular pressure (IOP) or AH outflow is unknown. The current study addresses this question using transgenic mice expressing human GDF15 and GDF15 null mice, and by perfusing enucleated mouse eyes with recombinant human GDF15. Treatment of primary cultures of human trabecular meshwork (TM) cells either with a telomerase inhibitor, an ER (endoplasmic reticulum) stress inducing agent, hydrogen peroxide, or an autophagy inhibitor, resulted in significant elevation in GDF15 levels relative to the respective control cells. Recombinant human GDF15 stimulated modest but significant increases in expression of genes encoding the extracellular matrix, cell adhesion proteins, and chemokine receptor (CCR2) in human TM cells compared to controls, as deduced from differential transcriptional profiles by RNAseq analysis. There was a significant increase in IOP in transgenic mice expressing human GDF15, but not in GDF15 null mice, compared to the respective wild type control mice. AH outflow facility was decreased in enucleated wild type mouse eyes perfused with recombinant human GDF15. Light microcopy based histological examination of the conventional AH outflow pathway tissues did not reveal identifiable differences between the GDF15 targeted and control mice. Taken together, these results reveal modest elevations of IOP in mice expressing human GDF15 possibly stemming from decreased aqueous humor outflow through the trabecular pathway.