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Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease.
MedLine Citation:
PMID:  24947415     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS: The mechanisms responsible for renal injury in atherosclerotic renovascular disease (ARVD) are incompletely understood, and few therapeutic options are available to reverse it. We hypothesized that chronic renal damage involves mitochondrial injury, and that mitochondrial protection would reduce renal fibrosis and dysfunction in ARVD pigs.
METHODS AND RESULTS: Domestic pigs were studied after 10 weeks of ARVD or sham, treated for the last 4 weeks with daily SC injections (5d/wk) of vehicle or Bendavia (0.1 mg/kg), a tetrapeptide that preserves cardiolipin content in the mitochondrial inner membrane. Single-kidney hemodynamics and function were studied using fast-CT, oxygenation using blood-oxygen-level-dependent (BOLD) MRI, and microvascular architecture, oxidative stress, and fibrosis ex-vivo. Cardiolipin content was assessed using mass-spectrometry and staining. Renal endothelial function was studied in-vivo and ex-vivo. In addition, swine renal-artery-endothelial-cells (RAEC) incubated with tert-butyl-hydroperoxide (tBHP) were also treated with Bendavia. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) decreased in ARVD+Vehicle compared to normal (318.8±61.0 vs. 553.8±82.8 ml/min and 48.0±4.0 vs. 84.0±3.8 ml/min, respectively) associated with loss of cardiolipin, intra-renal microvascular rarefaction, and hypoxia. Bendavia restored cardiolipin content in ARVD and improved vascular density, oxygenation, RBF (535.1±24.9 ml/min), and GFR (86.6±11.2 ml/min). Oxidative stress and fibrosis were ameliorated, and renovascular endothelial function normalized both in-vivo and in-vitro.
CONCLUSION: Preservation of mitochondrial cardiolipin attenuated swine stenotic-kidney microvascular loss and injury, and improved renal oxygenation, hemodynamics and function. These observations implicate mitochondrial damage in renal deterioration in chronic experimental ARVD, and position the mitochondria as a central therapeutic target.
Authors:
Alfonso Eirin; Behzad Ebrahimi; Xin Zhang; Xiang-Yang Zhu; John R Woollard; Quan He; Stephen C Textor; Amir Lerman; Lilach O Lerman
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-6-19
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2014 Jun 
Date Detail:
Created Date:  2014-6-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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