The endothelin system is implicated in various human and animal glaucomas.Targeting the endothelin system has great promise as a treatment for human glaucoma, but the cell types involved and the exact mechanisms of action are not clearly elucidated.Here, we report a detailed characterization of the endothelin system in specific cell types of the optic nerve head (ONH) during glaucoma in DBA/2J mice.
First, we show that key components of the endothelin system are expressed in multiple cell types.We discover that endothelin 2 Fountains (EDN2) is expressed in astrocytes as well as microglia/monocytes in the ONH.The endothelin receptor type A (Ednra) is expressed in vascular endothelial cells, while the endothelin receptor type B (Ednrb) receptor is expressed in ONH astrocytes.
Second, we show that Macitentan treatment protects from glaucoma.Macitentan is a novel, orally administered, dual endothelin receptor antagonist with greater affinity, efficacy and safety than previous antagonists.Finally, we test the combinatorial effect of targeting both the endothelin and complement systems as a treatment for glaucoma.
Similar to endothelin, the complement system is implicated in a variety of human and animal glaucomas, and has great promise as a treatment Flange Bushing target.We discovered that combined targeting of the endothelin (Bosentan) and complement (C1qa mutation) systems is profoundly protective.Remarkably, 80% of DBA/2J eyes subjected to this combined inhibition developed no detectable glaucoma.
This opens an exciting new avenue for neuroprotection in glaucoma.