Mitochondrial targeted ROS scavenger based on nitroxide for treatment and MRI imaging of acute kidney injury

Abstract

Overproduction of reactive oxygen species (ROS) during oxidative stress is hallmark of acute kidney injury (AKI), which induced the damage to the renal cells and mitochondrial injury. In this contribution, we prepared mitochondrial targeted nitroxide, which linked 3-carboxy-2,2,5,5-tetramethylpyrrolidine 1-oxyl (carboxy-PROXYL) with (2-aminoethyl)triphenylphosphonium bromide (TPP), named TPP-PROXYL to eliminate the ROS in situ and image the oxidative stress reaction by MRI. 2,7-Dichlorodi-hydrofluorescein diacetate (DCFH-DA) staining, mitochondrial membrane potential assay (JC-1) staining and transmission electron microscope (TEM) experiments were processed to verify that TPP-PROXYL could target mitochondria, scavenge the ROS, and prevent damage to mitochondria in live cells. Contrast enhanced MRI also been used to monitor these redox reaction in AKI model. TPP-PROXYL demonstrated excellent ROS T₁-weighted magnetic resonance imaging enhancement in vitro and in vivo, with r₁ value about 0.190 mM⁻¹ s⁻¹. In vivo AKI treatment experiments proved that TPP-PROXYL could improve the survival rate of mice and inhibit kidney damage. Moreover, the great ROS scavenging capability and the renal damage reduction during AKI treatment of TPP-PROXYL was verified via MR imaging technology. Collectively, this research provides TPP-PROXYL would serve as a powerful platform to realize ROS scavenging, treatment, and MR imaging of AKI.

Keywords:

• Acute kidney injury
• nitroxide
• mitochondrial targeted
• MRI
• redox reaction
• ROS scavenging

Ethics approval

Animal experiments are in accordance with the regulations of the Animal Ethical and Welfare Committee of Southern Medical University (SYXK 2016-0167).

Consent for publication

All authors agreed to publish the manuscript.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Quan Tao, Di Zhang, Qianqian Zhang, Chuang Liu, Yanqiu Feng and Ruiyuan Liu. The first draft of the manuscript was written by Quan Tao, Yanqiu Feng and Ruiyuan Liu. All authors commented on previous versions of the manuscript and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data that support the findings of this study are available from the corresponding author

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [NSFC; Grant Numbers: 81671749, 81871349].