Abstract
The majority of kidneys used for transplantation are obtained from deceased donors. These kidneys must undergo cold preservation/storage before transplantation to preserve tissue quality and allow time for recipient selection and transport. However, cold storage (CS) can result in tissue injury, kidney discardment, or long-term renal dysfunction after transplantation. We have previously determined mitochondrial superoxide and other downstream oxidants to be important signaling molecules that contribute to CS plus rewarming (RW) injury of rat renal proximal tubular cells. Thus, this study's purpose was to determine whether adding mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to University of Wisconsin (UW) preservation solution could offer protection against CS injury. CS was initiated by placing renal cells or isolated rat kidneys in UW solution alone (4 h at 4°C) or UW solution containing MitoQ or its control compound, decyltriphenylphosphonium bromide (DecylTPP) (1 μM in vitro; 100 μM ex vivo). Oxidant production, mitochondrial function, cell viability, and alterations in renal morphology were assessed after CS exposure. CS induced a 2- to 3-fold increase in mitochondrial superoxide generation and tyrosine nitration, partial inactivation of mitochondrial complexes, and a significant increase in cell death and/or renal damage. MitoQ treatment decreased oxidant production ∼2-fold, completely prevented mitochondrial dysfunction, and significantly improved cell viability and/or renal morphology, whereas DecylTPP treatment did not offer any protection. These findings implicate that MitoQ could potentially be of therapeutic use for reducing organ preservation damage and kidney discardment and/or possibly improving renal function after transplantation.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.176743.
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ABBREVIATIONS:
- CS
- cold storage
- RW
- rewarming
- DecylTPP
- decyltriphenylphosphonium bromide
- I/R
- ischemia/reperfusion
- LDH
- lactate dehydrogenase
- MitoQ
- mitoquinone
- NOS
- nitric-oxide synthase
- NRK
- normal rat kidney
- ROS
- reactive oxygen species
- UW
- University of Wisconsin
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick end labeling
- DMEM
- Dulbecco's modified Eagle's medium
- FCS
- fetal calf serum
- Untx
- untreated
- PBS
- phosphate-buffered saline
- TdT
- terminal deoxynucleotidyl transferase.
- Received October 29, 2010.
- Accepted December 14, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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