Mitochondria‐Targeted Antioxidants: Future Perspectives in Kidney Ischemia Reperfusion Injury

Abstract

Kidney ischemia/reperfusion injury emerges in various clinical settings as a great problem complicating the course and outcome. Ischemia/reperfusion injury is still an unsolved puzzle with a great diversity of investigational approaches, putting the focus on oxidative stress and mitochondria. Mitochondria are both sources and targets of ROS. They participate in initiation and progression of kidney ischemia/reperfusion injury linking oxidative stress, inflammation, and cell death. The dependence of kidney proximal tubule cells on oxidative mitochondrial metabolism makes them particularly prone to harmful effects of mitochondrial damage. The administration of antioxidants has been used as a way to prevent and treat kidney ischemia/reperfusion injury for a long time. Recently a new method based on mitochondria-targeted antioxidants has become the focus of interest. Here we review the current status of results achieved in numerous studies investigating these novel compounds in ischemia/reperfusion injury which specifically target mitochondria such as MitoQ, Szeto-Schiller (SS) peptides (Bendavia), SkQ1 and SkQR1, and superoxide dismutase mimics. Based on the favorable results obtained in the studies that have examined myocardial ischemia/reperfusion injury, ongoing clinical trials investigate the efficacy of some novel therapeutics in preventing myocardial infarct. This also implies future strategies in preventing kidney ischemia/reperfusion injury.

Alternative Interventions to Prevent Oxidative Damage following Ischemia/Reperfusion

“…This increase triggers the activation of Na + /H + exchangers that consequently results in an increase in H + and changes the pH of the cell. These events impair the metabolic processes of the cell and affect K + channels in mitochondria [21, 23, 33, 64, 100, 101, 107–115]. …”

“…The efflux of H + produces an influx of Na + increasing the concentration of Na + in the cytosol. This increase activates the Na + /Ca +2 exchanger, which leads to an increase in cytosolic Ca +2 [21, 23, 33, 64, 100, 101, 107–115]. The high concentration of Ca +2 in the cytosol activates several proteases and other proteins that lead to dysfunction and destruction of organelle membranes and corruption of normal metabolism [21, 23, 33, 64, 100, 101, 107–115].…”

“…In the kidney, glomerular charge is inverted and overloads filtration solutes, increasing water, protein, and electrolyte loss through urine production. In hepatocytes, membrane potential and pH changes are detected, which suppress and activate many enzymes that optimally operate at a neutral pH, and lead to edema and necrosis [21, 23, 33, 64, 100, 101, 107–115]. …”

“…The high concentration of Ca +2 activates mitochondrial calcium-sensitive K + channels (mtKca) and mitochondrial nitric oxide synthase (mtNOS), which increases the levels of nitric oxide (NO • ) (Figure 3) [21, 23, 33, 64, 100, 101, 107–115]. NO • blocks complex IV in the respiratory chain, inducing an influx of electrons into the mitochondrial matrix and depletion of ATP.…”

“…NO • reduces molecules to superoxide anions (O 2 − ) and produces high levels of peroxynitrite (ONOO − ). The loss of ATP is caused by the impairment to ATP recycling, depletion of substrates, and inhibition of complex IV in the respiratory chain [21, 23, 33, 64, 100, 101, 107–116]. This influx of electrons into the mitochondrial matrix and the efflux of protons to the cytosol maintains mitochondrial membrane potential; however, it results in an increase in the production of ROS, RNS, and edema and makes the mitochondrial matrix an alkaline environment [21, 23, 33, 64, 100, 101, 107–116].…”