Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease

Alfonso Eirin, Behzad Ebrahimi, Xin Zhang, Xiang Yang Zhu, John R. Woollard, Quan He, Stephen C Textor, Amir Lerman, Lilach O Lerman

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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 pigswere studied after 10 weeks of ARVDor sham, treated for the last 4weeks with daily subcutaneous injections (5 days/week) of vehicle or Bendavia (0.1 mg/kg), a tetrapeptide that preserves cardiolipin content in the mitochondrial inner membrane. Single-kidney haemodynamics and function were studied using fast-computer tomography, oxygenation using blood oxygen level-dependent magnetic resonance imaging, 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 incubated with tert-butyl hydroperoxide were also treated with Bendavia. Stenotic-kidney renal blood flow(RBF) and glomerular filtration rate (GFR) decreased in ARVD + Vehicle compared with 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, haemodynamics, and function. These observations implicate mitochondrial damage in renal deterioration in chronic experimental ARVD, and position the mitochondria as a central therapeutic target.

Original languageEnglish (US)
Pages (from-to)461-472
Number of pages12
JournalCardiovascular Research
Volume103
Issue number4
DOIs
StatePublished - 2014

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Swine
Kidney
Cardiolipins
Fibrosis
Renal Circulation
Glomerular Filtration Rate
Wounds and Injuries
Oxidative Stress
Hemodynamics
tert-Butylhydroperoxide
Mitochondrial Membranes
Renal Artery
Subcutaneous Injections
Vascular Diseases
Mass Spectrometry
Mitochondria
Endothelial Cells
Tomography
Magnetic Resonance Imaging
Staining and Labeling

Keywords

  • Atherosclerosis
  • Hypertension
  • Mitochondria
  • Renal

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. / Eirin, Alfonso; Ebrahimi, Behzad; Zhang, Xin; Zhu, Xiang Yang; Woollard, John R.; He, Quan; Textor, Stephen C; Lerman, Amir; Lerman, Lilach O.

In: Cardiovascular Research, Vol. 103, No. 4, 2014, p. 461-472.

Research output: Contribution to journalArticle

Eirin, Alfonso ; Ebrahimi, Behzad ; Zhang, Xin ; Zhu, Xiang Yang ; Woollard, John R. ; He, Quan ; Textor, Stephen C ; Lerman, Amir ; Lerman, Lilach O. / Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. In: Cardiovascular Research. 2014 ; Vol. 103, No. 4. pp. 461-472.
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AU - Ebrahimi, Behzad

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AU - Woollard, John R.

AU - He, Quan

AU - Textor, Stephen C

AU - Lerman, Amir

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N2 - 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 pigswere studied after 10 weeks of ARVDor sham, treated for the last 4weeks with daily subcutaneous injections (5 days/week) of vehicle or Bendavia (0.1 mg/kg), a tetrapeptide that preserves cardiolipin content in the mitochondrial inner membrane. Single-kidney haemodynamics and function were studied using fast-computer tomography, oxygenation using blood oxygen level-dependent magnetic resonance imaging, 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 incubated with tert-butyl hydroperoxide were also treated with Bendavia. Stenotic-kidney renal blood flow(RBF) and glomerular filtration rate (GFR) decreased in ARVD + Vehicle compared with 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, haemodynamics, and function. These observations implicate mitochondrial damage in renal deterioration in chronic experimental ARVD, and position the mitochondria as a central therapeutic target.

AB - 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 pigswere studied after 10 weeks of ARVDor sham, treated for the last 4weeks with daily subcutaneous injections (5 days/week) of vehicle or Bendavia (0.1 mg/kg), a tetrapeptide that preserves cardiolipin content in the mitochondrial inner membrane. Single-kidney haemodynamics and function were studied using fast-computer tomography, oxygenation using blood oxygen level-dependent magnetic resonance imaging, 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 incubated with tert-butyl hydroperoxide were also treated with Bendavia. Stenotic-kidney renal blood flow(RBF) and glomerular filtration rate (GFR) decreased in ARVD + Vehicle compared with 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, haemodynamics, and function. These observations implicate mitochondrial damage in renal deterioration in chronic experimental ARVD, and position the mitochondria as a central therapeutic target.

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KW - Mitochondria

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