Influence of Warm Ischemia Time on Peripheral-Type Benzodiazepine Receptor: A New Aspect of the Role of Mitochondria

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Abstract

The peripheral benzodiazepine receptor (PBR) is located mainly in the outer mitochondrial membrane and many functions are associated directly or indirectly with the PBR. We have studied the influence of different durations of warm ischemia (WI) on renal function, tissue damage and PBR expression in a Large Whitepig model. After a midline incision, the renal pedicle was clamped for 10 (WI10), 30 (WI30), 45 (WI45), 60 (WI60) or 90 min (WI90), and blood and renal tissue samples were collected between 1 day and 2 weeks after reperfusion for assessment of renal function. Metabolite excretion associated with renal ischemia reperfusion injury such as trimethylamine- N-oxide (TMAO) was quantified in blood by magnetic resonance spectroscopy. PBR mRNA and protein expression were determined in renal tissue. TMAO levels rose progressively and significantly with increasing duration of WI. PBR mRNA expression was upregulated between 3 h and 1 day after reperfusion in WI30, WI45 and WI60. Its upregulation was noted 3 days after reperfusion in WI90. At day 14, PBR transcript expression was not different from basal level in any group. PBR protein followed the same pattern. These findings suggest a new role for PBR which could be a major target in the regeneration process during ischemia reperfusion.

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Recent advances in the pathophysiology of ischemic acute renal failure.

M. Weinberg, Joseph V. Bonventre (2003)

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Mitochondrial permeability transition: a common pathway to necrosis and apoptosis.

Jae-Sung Kim, Lihua He, John Lemasters (2003)

Opening of high conductance permeability transition pores in mitochondria initiates onset of the mitochondrial permeability transition (MPT). The MPT is a causative event, leading to necrosis and apoptosis in hepatocytes after oxidative stress, Ca(2+) toxicity, and ischemia/reperfusion. CsA blocks opening of permeability transition pores and protects cell death after these stresses. In contrast to necrotic cell death which is a consequence of ATP depletion, ATP is required for the development of apoptosis. Reperfusion and the return of normal pH after ischemia initiate the MPT, but the balance between ATP depletion after the MPT and ATP generation by glycolysis determines whether the fate of cells will be apoptotic or necrotic death. Thus, the MPT is a common pathway leading to both necrotic and apoptotic cell death after ischemia/reperfusion.

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The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development.

Moshe Gavish, Leo Veenman (2006)

Peripheral-type benzodiazepine receptors (PBRs) are abundant in the cardiovascular system. In the cardiovascular lumen, PBRs are present in platelets, erythrocytes, lymphocytes, and mononuclear cells. In the walls of the cardiovascular system, PBR can be found in the endothelium, the striated cardiac muscle, the vascular smooth muscles, and the mast cells. The subcellular location of PBR is primarily in mitochondria. The PBR complex includes the isoquinoline binding protein (IBP), voltage-dependent anion channel (VDAC), and adenine nucleotide transporter (ANT). Putative endogenous ligands for PBR include protoporphyrin IX, diazepam binding inhibitor (DBI), triakontatetraneuropeptide (TTN), and phospholipase A2 (PLA2). Classical synthetic ligands for PBR are the isoquinoline 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide (PK 11195) and the benzodiazepine 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5 4864). Novel PBR ligands include N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), both possessing steroidogenic properties, but while FGIN-1-27 is pro-apoptotic, SSR180575 is anti-apoptotic. Putative PBR functions include regulation of steroidogenesis, apoptosis, cell proliferation, the mitochondrial membrane potential, the mitochondrial respiratory chain, voltage-dependent calcium channels, responses to stress, and microglial activation. PBRs in blood vessel walls appear to take part in responses to trauma such as ischemia. The irreversible PBR antagonist, SSR180575, was found to reduce damage correlated with ischemia. Stress, anxiety disorders, and neurological disorders, as well as their treatment, can affect PBR levels in blood cells. PBRs in blood cells appear to play roles in several aspects of the immune response, such as phagocytosis and the secretion of interleukin-2, interleukin-3, and immunoglobulin A (IgA). Thus, alterations in PBR density in blood cells may have immunological consequences in the affected person. In conclusion, PBR in the cardiovascular system may represent a new target for drug development.

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Author and article information

Journal

Journal ID (publisher-id): NEE

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2007

Publication date (Print): September 2007

Publication date (Electronic): 05 July 2007

Volume: 107

Issue: 1

Pages: e1-e11

Affiliations

^aInserm, E0 324, Poitiers and Université Poitiers, Poitiers, ^bINRA, Unité de Transplantation Expérimentale, Département de Génétique Animale, Domaine du Magneraud, Surgères, ^cService d’Anatomopathologie, Centre Hospitalier et Universitaire, and ^dEA 3807, Université Poitiers, France; ^eDepartment of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C., USA

Article

Publisher ID: 105139 Other ID: Nephron Exp Nephrol 2007;107:e1–e11

DOI: 10.1159/000105139

PubMed ID: 17622771

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