Involvement of Peripheral Benzodiazepine Receptor in the Oxidative Stress, Death-Signaling Pathways, and Renal Injury Induced by Ischemia-Reperfusion

Abstract

The peripheral benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell death. In the present study we investigated the role of PBR in the regulation of signaling pathways leading to apoptotic and necrotic damage and renal dysfunction in a rat model of ischemia-reperfusion. Renal ischemia-reperfusion led to extended tubular apoptosis and necrosis that were associated with peroxidative damage, high levels of proapoptotic Bax expression, and low levels of antiapoptotic Bcl-2 expression, cleavage of death substrate, poly(ADP-ribose) polymerase (PARP), and activation of a key effector of apoptosis, caspase-3. Rat pretreatment with a novel PBR antagonist, SSR180575, significantly decreased postreperfusion oxidative stress and tubular apoptosis and necrosis. This effect was associated with inhibition of caspase-3 activation and PARP cleavage, upregulation of Bcl-2, and downregulation of Bax. Furthermore, inhibition of PBR accelerated the recovery of normal renal function, as assessed by measurement of levels of plasma creatinine and blood urea nitrogen. These findings reveal a role for PBR as a modulator of necrotic and apoptotic cell death induced by ischemia-reperfusion and suggest that regulation of PBR may provide new therapeutic implications for the prevention of acute renal failure.

A p38 mitogen-activated protein kinase inhibitor protects against renal damage in a non-heart-beating donor model

“…The involvement of PBR and its ligands in G1/S arrest is well-documented (40,41). Recently, PBR antagonist ligands were shown to interact with p38-MAPK to mediate apoptosis and cell cycle arrest (23). The current study suggests that functional preservation of PBR is important during the regeneration process as previously suggested (52,53).…”

The Effect of Diazepam on the Function of Hypertrophied Rats’ Hearts in Ischemia-Reperfusion Conditions

“…This showed the relative reduction of CMI% in the presence of diazepam. Consistently, several studies have shown that the presence of PBR ligands, including Ro5-4864 and SSR180575, could reduce oxidative stress, thereby preventing cardiac hypertrophy (3,23,24). Oxidative stress is implicated in development and progression of cardiac hypertrophy (25).…”

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

“…Consistent with its localization in the MPTP, TSPO is involved in the regulation of apoptosis, but also in the regulation of cell proliferation, stimulation of steroidogenesis, immunomodulation, porphyrin transport, heme biosynthesis, anion transport and regulation of mitochondrial functions [7]. Previous studies have demonstrated that, after 45 min of WI and 6 h of reperfusion, the irreversible TSPO antagonist SSR180575 reduces renal damage by modulation of necrotic and apoptoticcell death induced by IR [8]. In turn, the classical TSPO ligand PK11195 may exacerbate or prevent damage caused by ischemia or have no effect.…”