title: Dysfunction of Kidney Endothelium after Ischemia/Reperfusion and Its Prevention by Mitochondria-Targeted Antioxidant.
abstract: One of the most important pathological consequences of renal ischemia/reperfusion (I/R) is kidney malfunctioning. I/R leads to oxidative stress, which affects not only nephron cells but also cells of the vascular wall, especially endothelium, resulting in its damage. Assessment of endothelial damage, its role in pathological changes in organ functioning, and approaches to normalization of endothelial and renal functions are vital problems that need to be resolved. The goal of this study was to examine functional and morphological impairments occurring in the endothelium of renal vessels after I/R and to explore the possibility of alleviation of the severity of these changes using mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decylrhodamine 19 (SkQR1). Here we demonstrate that 40-min ischemia with 10-min reperfusion results in a profound change in the structure of endothelial cells mitochondria, accompanied by vasoconstriction of renal blood vessels, reduced renal blood flow, and increased number of endothelial cells circulating in the blood. Permeability of the kidney vascular wall increased 48 h after I/R. Injection of SkQR1 improves recovery of renal blood flow and reduces vascular resistance of the kidney in the first minutes of reperfusion; it also reduces the severity of renal insufficiency and normalizes permeability of renal endothelium 48 h after I/R. In in vitro experiments, SkQR1 provided protection of endothelial cells from death provoked by oxygen-glucose deprivation. On the other hand, an inhibitor of NO-synthases, L-nitroarginine, abolished the positive effects of SkQR1 on hemodynamics and protection from renal failure. Thus, dysfunction and death of endothelial cells play an important role in the development of reperfusion injury of renal tissues. Our results indicate that the major pathogenic factors in the endothelial damage are oxidative stress and mitochondrial damage within endothelial cells, while mitochondria-targeted antioxidants could be an effective tool for the protection of tissue from negative effects of ischemia.
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow, 119991, Russia. zorov@genebee.msu.ru.
authors.forename: S S
authors.initials: SS
authors.lastname: Jankauskas
authors.forename: N V
authors.initials: NV
authors.lastname: Andrianova
authors.forename: I B
authors.initials: IB
authors.lastname: Alieva
authors.forename: A N
authors.initials: AN
authors.lastname: Prusov
authors.forename: D D
authors.initials: DD
authors.lastname: Matsievsky
authors.forename: L D
authors.initials: LD
authors.lastname: Zorova
authors.forename: I B
authors.initials: IB
authors.lastname: Pevzner
authors.forename: E S
authors.initials: ES
authors.lastname: Savchenko
authors.forename: Y A
authors.initials: YA
authors.lastname: Pirogov
authors.forename: D N
authors.initials: DN
authors.lastname: Silachev
authors.forename: E Y
authors.initials: EY
authors.lastname: Plotnikov
authors.forename: D B
authors.initials: DB
authors.lastname: Zorov
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects; D015687:Cell Hypoxia; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006339:Heart Rate; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D010971:Plastoquinone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D012235:Rhodamines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C534903:10-(6'-plastoquinonyl) decylrhodamine 19; D000975:Antioxidants; D012235:Rhodamines; D010971:Plastoquinone