Induction of the cystine/glutamate exchanger SLC7A11 in retinal pigment epithelial cells by the antipsoriatic drug monomethylfumarate

PURPOSE. Oxidative stress is a common pathological factor in degenerative retinal diseases; therefore, identifying novel strategies for its limitation is critically important and highly relevant clinically. Along these lines, our present goal was to evaluate the effect(s) of the fumarate ester and antipsoriatic agent monomethylfumarate (MMF) on the expression and functional activity of the cystine/glutamate exchanger SLC7A11 (system x_c^-), a transport system critical to potentiation of antioxidant signaling in retina. METHODS. ARPE-19 and primary mouse RPE cells were cultured in the presence or absence of varying concentrations of MMF (0-5000 μM) for 0 to 24 hours. MMF (10 mM) was also delivered intravitreally to mouse eyes. RT-PCR, radiolabeled uptake, Western blotting, and glutathione (GSH) assays were then used to evaluate the effects of MMF on endogenous antioxidant machinery. RESULTS. MMF induced system x_c^-, Nrf2, and hypoxia-inducible factor 1α (Hif-1α) in cultured RPE cells. Additionally, the compound was recognized as a transportable substrate by the Na₊-coupled monocarboxylate transporter SLC5A8 (SMCT1). In vivo these factors were evidenced by a significant increase in retinal levels of GSH. CONCLUSIONS. MMF stimulates multiple pathways in retinal cells that potentiate cellular events leading to the upregulation of genes/mechanisms that function to protect retina against various forms of insult; upregulation of system x_c^- is one such consequence. To our knowledge, this is the first report that fumarate esters, compounds already employed clinically for other indications, are effective in retina via x_c^- induction. This novel, hitherto unknown mechanism helps to explain the antioxidant feature of these compounds and highlights their therapeutic potential in retina.