Mechanisms of nephroprotective effect of mitochondria-targeted antioxidants under rhabdomyolysis and ischemia/reperfusion.
Oxidative stress-related renal pathologies apparently include rhabdomyolysis and ischemia/reperfusion phenomenon. These two pathologies were chosen for study in order to develop a proper strategy for protection of the kidney. Mitochondria were found to be a key player in these pathologies, being both the source and the target for excessive production of reactive oxygen species (ROS). A mitochondria-targeted compound which is a conjugate of a positively charged rhodamine molecule with plastoquinone (SkQR1) was found to rescue the kidney from the deleterious effect of both pathologies. Intraperitoneal injection of SkQR1 before the onset of pathology not only normalized the level of ROS and lipid peroxidized products in kidney mitochondria but also decreased the level of cytochrome c in the blood, restored normal renal excretory function and significantly lowered mortality among animals having a single kidney exposed to ischemia/reperfusion. The SkQR1-derivative missing plastoquinone (C12R1) possessed some, although limited nephroprotective properties and enhanced animal survival after ischemia/reperfusion. SkQR1 was found to induce some elements of nephroprotective pathways providing ischemic tolerance such as an increase in erythropoietin levels and phosphorylation of glycogen synthase kinase 3β in the kidney. SkQR1 also normalized renal erythropoietin level lowered after kidney ischemia/reperfusion and injection of a well-known nephrotoxic agent gentamicin.
Plotnikov
E Y
EY
Laboratory of Mitochondrial Structure and Functions, AN Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119991 Russia.
Chupyrkina
A A
AA
Jankauskas
S S
SS
Pevzner
I B
IB
Silachev
D N
DN
Skulachev
V P
VP
Zorov
D B
DB
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D004921:Erythropoietin / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010971:Plastoquinone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D015427:Reperfusion Injury / Q000150:complications*; D012206:Rhabdomyolysis / Q000150:complications*; D012235:Rhodamines / Q000737:chemistry / Q000494:pharmacology*; D015996:Survival Rate
C534903:10-(6'-plastoquinonyl) decylrhodamine 19; D000975:Antioxidants; D020011:Protective Agents; D012235:Rhodamines; D004921:Erythropoietin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D010971:Plastoquinone