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Author Notes:

Correspondence: Dr. W. Robert Taylor, Division of Cardiology, Department of Medicine, Emory University School of Medicine, 1639 Pierce Drive, Suite 319 WMB, Atlanta, GA 30322. Email: wtaylor@emory.edu.

Plasma creatinine and BUN levels were measured by Dr. James Ritchie, Department of Pathology, Emory University.

The tempol-folate conjugate described in this study is contained in patent application number WO2011/037913 assigned to Emory University.

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Research Funding:

This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, as a Program of Excellence in Nanotechnology Award (N01 HV-08234) to W.R.T.

Folate Receptor-Targeted Antioxidant Therapy Ameliorates Renal Ischemia-Reperfusion Injury

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Journal Title:

Journal of the American Society of Nephrology

Volume:

Volume 23, Number 5

Publisher:

, Pages 793-800

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2012 by the American Society of Nephrology

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