GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients
Norimitsu Ban, Carla J. Siegfried, Jonathan B. Lin, Ying-Bo Shui, Julia Sein, Wolfgang Pita-Thomas, Abdoulaye Sene, Andrea Santeford, Mae Gordon, Rachel Lamb, Zhenyu Dong, Shannon C. Kelly, Valeria Cavalli, Jun Yoshino, Rajendra S. Apte
Norimitsu Ban, Carla J. Siegfried, Jonathan B. Lin, Ying-Bo Shui, Julia Sein, Wolfgang Pita-Thomas, Abdoulaye Sene, Andrea Santeford, Mae Gordon, Rachel Lamb, Zhenyu Dong, Shannon C. Kelly, Valeria Cavalli, Jun Yoshino, Rajendra S. Apte
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Research Article Ophthalmology

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

Abstract

Glaucoma is the second leading cause of blindness worldwide. Physicians often use surrogate endpoints to monitor the progression of glaucomatous neurodegeneration. These approaches are limited in their ability to quantify disease severity and progression due to inherent subjectivity, unreliability, and limitations of normative databases. Therefore, there is a critical need to identify specific molecular markers that predict or measure glaucomatous neurodegeneration. Here, we demonstrate that growth differentiation factor 15 (GDF15) is associated with retinal ganglion cell death. Gdf15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons and in a murine chronic glaucoma model. We also demonstrate that the ganglion cell layer may be one of the sources of secreted GDF15 and that GDF15 diffuses to and can be detected in aqueous humor (AH). In validating these findings in human patients with glaucoma, we find not only that GDF15 is increased in AH of patients with primary open angle glaucoma (POAG), but also that elevated GDF15 levels are significantly associated with worse functional outcomes in glaucoma patients, as measured by visual field testing. Thus, GDF15 maybe a reliable metric of glaucomatous neurodegeneration, although further prospective validation studies will be necessary to determine if GDF15 can be used in clinical practice.

Authors

Norimitsu Ban, Carla J. Siegfried, Jonathan B. Lin, Ying-Bo Shui, Julia Sein, Wolfgang Pita-Thomas, Abdoulaye Sene, Andrea Santeford, Mae Gordon, Rachel Lamb, Zhenyu Dong, Shannon C. Kelly, Valeria Cavalli, Jun Yoshino, Rajendra S. Apte

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Figure 3

Ganglion cell layer (GCL) showed increased Gdf15 expression following axonal injury to the optic nerve.

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Ganglion cell layer (GCL) showed increased Gdf15 expression following ax...
(A) In situ hybridization of Gdf15 in the mid peripheral retina (n = 3 per group, representative pictures are shown). ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. Scale bar: 50 μm. (B and C) Gene expression of Gdf15 in anterior segment (AS), lens, and retina (B) 6 hours (n = 3 per group) and (C) 24 hours after optic nerve crush (ONC) (n = 6 per group). (D) In situ hybridization of Gdf15 in the mid-peripheral retina 24 hours after ONC (n = 4 per group, representative pictures are shown). Scale bar: 50 μm. (E–G) High-magnification images from D. Scale bar: 50 μm. (E) In situ hybridization of Gdf15 24 hours after ONC in GCL. (F) In situ hybridization of Gdf15 24 hours after ONC in INL. (G) In situ hybridization of Gdf15 24 hours after ONC in ONL. (H) Gdf15 gene expression in GCL, INL, and ONL of the retina following the isolation by laser microdissection 24 hours after ONC (n = 4 per group). (I and J) F4/80 gene expression in the retina (I) 6 hours (n = 3 per group) and (J) 24 hours after ONC (n = 5 per group). Values are mean ± SD. ***P < 0.001 by 2-tailed unpaired t test.