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.

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

“…TEMPOL has been shown to reduce post-ischemic inflammatory signaling in a rat [54] and mouse [57] model of renal I/R and a Guinea pig model of gallbladder I/R [56]. Oxidative stress and cell death during I/R lead to highly pleiotropic immune signaling and sterile inflammation [9], which was confirmed in our model on the basis of the IL-6 ( Figure 3B) and MPO data ( Figure 3G, H).…”

“…Accordingly, numerous studies have shown that TEMPOL reduces I/R AKI in different species, including rats [54]. The antioxidant [55], immunosuppressive [56,57], and AKIameliorating effects of TEMPOL are well-established in I/R AKI. Conversely, relatively little information is available in terms of renal oxygenation, which is critical for renal function [8].…”

Folate-mediated chemotherapy and diagnostics: An updated review and outlook

“…Recently, a folate-antioxidant conjugate (5-hydroxy-Tempo-folate) was synthesized to ameliorate renal ischemia/reperfusion injury (IRI). Such Tempo-folate conjugate was designed to target FRα-highly expressed proximal tubular epithelia, where the predominant site of injury occurred during and after IRI [82]. The third question is how to prevent FA-decorated nanoparticles to be filtered from glomeruli to prolong the circulation time for systemic targeted chemotherapy, perhaps by increasing the size and PEGylation of the nanoparticles.…”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…In this regard, antioxidants are known to mitigate ischemia-reperfusion injury [44,45]. To limit the non-selective target of antioxidant therapy and to avoid the high dose of antioxidants necessary to achieve effective local concentrations, a research team has recently demonstrated that complexation of the membrane-permeable superoxide dismutase mimetic 4-hydroxy-Tempo (Tempol) to folate specifically targeted the renal proximal tubules, due to their expression of high levels of folate receptors, -and limited ischemia-reperfusion injury [46]. The preservation period represents a critical therapeutic time window.…”