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Technical Refinement of a Bilateral Renal Ischemia-Reperfusion Mouse Model for Acute Kidney Injury Research
Published on: November 3, 2023
Folate receptor-targeted antioxidant therapy ameliorates renal ischemia-reperfusion injury
Sarah F Knight1, Kousik Kundu, Giji Joseph
1Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
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.
Insights
Targeting antioxidants to the kidney using folate receptors protects against ischemic injury. This novel approach, tempol-folate, effectively scavenges superoxide and preserves renal function in mice.
Area of Science:
- Nephrology
- Biomedical Engineering
- Pharmacology
Background:
- Ischemic injury to the kidney is a significant clinical problem.
- Current antioxidant therapies lack kidney specificity, requiring high doses and leading to potential systemic side effects.
- Targeting therapies to specific kidney cells, like proximal tubule cells, is a promising strategy to improve efficacy and reduce toxicity.
Purpose of the Study:
- To develop a kidney-specific therapeutic strategy for preventing renal ischemic injury.
- To investigate the efficacy of a folate-conjugated antioxidant (tempol-folate) in targeting renal proximal tubule cells.
- To evaluate the protective effects of tempol-folate against ischemia-reperfusion injury in a mouse model.
Main Methods:
- Synthesis of a folate-antioxidant conjugate (tempol-folate) designed to target folate receptors highly expressed in renal proximal tubules.
- Assessment of the antioxidant capacity of conjugated tempol in proximal tubule cells using dihydroethidium high-performance liquid chromatography.
- Evaluation of tempol-folate's efficacy in a mouse model of renal ischemia-reperfusion injury, measuring superoxide levels, renal function, and macrophage infiltration.
- Confirmation of targeted delivery to the kidney using electron spin resonance.
Main Results:
- Conjugated tempol effectively scavenged superoxide in proximal tubule cells, retaining its antioxidant activity.
- Tempol-folate demonstrated superior reduction of renal superoxide levels compared to tempol alone in a mouse model of renal ischemia-reperfusion injury.
- Electron spin resonance confirmed successful targeting of tempol-folate to the kidney and other folate receptor-expressing tissues.
- Administration of tempol-folate significantly protected renal function and reduced macrophage infiltration following ischemia-reperfusion injury.
Conclusions:
- Kidney-specific targeting of antioxidants via folate receptors presents a viable therapeutic strategy for preventing renal ischemic injury.
- The developed tempol-folate conjugate is effective in reducing oxidative stress and protecting kidney function during ischemia-reperfusion.
- This targeted drug delivery approach holds potential for treating various kidney diseases by conjugating other pharmaceuticals to folate.
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