title: Folate receptor-targeted antioxidant therapy ameliorates renal ischemia-reperfusion injury.
abstract: Antioxidant therapy can protect against ischemic injury, but the inability to selectively target the kidney would require extremely high doses to achieve effective local concentrations of drug. Here, we developed a directed therapeutic that specifically targets an antioxidant to renal proximal tubule cells via the folate receptor. Because a local increase in superoxide contributes to renal ischemic injury, we created the folate-antioxidant conjugate 4-hydroxy-Tempo (tempol)-folate to target folate receptors, which are highly expressed in the proximal tubule. Dihydroethidium high-performance liquid chromatography demonstrated that conjugated tempol retained its efficacy to scavenge superoxide in proximal tubule cells. In a mouse model of renal ischemia-reperfusion injury, tempol-folate reduced renal superoxide levels more effectively than tempol alone. Furthermore, electron spin resonance revealed the successful targeting of the tempol-folate conjugate to the kidney and other tissues expressing folate receptors. Administration of tempol-folate protected the renal function of mice after ischemia-reperfusion injury and inhibited infiltration of macrophages. In conclusion, kidney-specific targeting of an antioxidant has therapeutic potential to prevent renal ischemic injury. Conjugation of other pharmaceuticals to folate may also facilitate the development of treatments for other kidney diseases.
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Knight
authors.forename: Kousik
authors.initials: K
authors.lastname: Kundu
authors.forename: Giji
authors.initials: G
authors.lastname: Joseph
authors.forename: Sergey
authors.initials: S
authors.lastname: Dikalov
authors.forename: Daiana
authors.initials: D
authors.lastname: Weiss
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000493:pharmacokinetics / Q000494:pharmacology; D058972:Folic Acid Transporters / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000098:blood supply*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D058972:Folic Acid Transporters; D013113:Spin Labels; D013481:Superoxides; C001803:tempol