title: Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury.
abstract: The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA. hhszeto@med.cornell.edu
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Soong
authors.forename: Dunli
authors.initials: D
authors.lastname: Wu
authors.forename: Shaun F
authors.initials: SF
authors.lastname: Darrah
authors.forename: Feng-Ying
authors.initials: FY
authors.lastname: Cheng
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Ganger
authors.forename: Clara Y
authors.initials: CY
authors.lastname: Tow
authors.forename: Surya V
authors.initials: SV
authors.lastname: Seshan
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D023421:Models, Animal; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000150:complications*
chemical_list: D000975:Antioxidants; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000255:Adenosine Triphosphate