title: Induction of the cystine/glutamate exchanger SLC7A11 in retinal pigment epithelial cells by the antipsoriatic drug monomethylfumarate.
abstract: OBJECTIVE
  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 xc(-)), 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 xc(-), 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 xc(-) 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 xc(-) induction. This novel, hitherto unknown mechanism helps to explain the antioxidant feature of these compounds and highlights their therapeutic potential in retina.
authors: Departments of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors: Sudha
authors: S
authors: Ananth
authors: Ellappan
authors: E
authors: Babu
authors: Rajalakshmi
authors: R
authors: Veeranan-Karmegam
authors: Brooke R
authors: BR
authors: Bozard Baldowski
authors: Thomas
authors: T
authors: Boettger
authors: Pamela M
authors: PM
authors: Martin
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003879:Dermatologic Agents / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005123:Eye / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008298:Maleates / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D015854:Up-Regulation
chemical_list: D027182:Amino Acid Transport System y+; D003879:Dermatologic Agents; D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008298:Maleates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; C492255:Slc7a11 protein, mouse; C073341:citraconic acid; D005978:Glutathione