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Attenuation of endoplasmic reticulum stress and mitochondrial injury in kidney with ischemic postconditioning application and trimetazidine treatment

Asma Mahfoudh-Boussaid1, Mohamed Amine Zaouali2, Thierry Hauet3, Kaouther Hadj-Ayed1, Abdel-Hédi Miled4, Sonia Ghoul-Mazgar5, Dalila Saidane-Mosbahi1, Joan Rosello-Catafau2 and Hassen Ben Abdennebi1*

Author Affiliations

1 Laboratory of human physiology, faculty of pharmacy, university of Monastir, Rue Avicenne, Monastir, 5000, Tunisia

2 Department of experimental pathology, Hepatic ischemia reperfusion unit, IIBB-CSIC, Barcelona, Spain

3 Inserm U927, faculty of medicine and pharmacy, university of Poitiers, Poitiers, France

4 Laboratory of biochemistry, faculty of pharmacy, university of Monastir, Monastir, Tunisia

5 Laboratory of histology and embryology, faculty of dental medicine, university of Monastir, Monastir, Tunisia

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Journal of Biomedical Science 2012, 19:71  doi:10.1186/1423-0127-19-71

Published: 1 August 2012

Abstract

Background

Endoplasmic reticulum (ER) and mitochondria have been implicated in the pathology of renal ischemia/reperfusion (I/R). In the present study, we investigated whether the use of ischemic postconditioning (IPostC) and trimetazidine (TMZ) separately or combined could reduce ER stress and mitochondria damage after renal ischemia.

Methods

Kidneys of Wistar rats were subjected to 60-min of warm ischemia followed by 120-min of reperfusion (I/R group, n = 6), or to 6 cycles of ischemia/reperfusion (10-s each cycle) just after 60-min of warm ischemia (IPostC group, n = 6), or to i.p. injection of TMZ (3 mg/kg) 30-min before ischemia (TMZ group, n = 6), or to the combination of both treatments (IPostC+TMZ group, n = 6). The results of these experimental groups were compared to those of a sham-operated group in which rat renal pedicles were only dissected. Sodium reabsorption rate, creatinine clearance lactate deshydrogenase (LDH) activity in plasma, and concentration of malonedialdehyde (MDA) in tissue were determined. In addition, Western blot analysis was performed to identify the amounts of cytochrome c, c-JunNH2-terminal kinase (JNK), voltage-dependent anion channel (VDAC), glycogen synthase kinase 3-beta (GSK3-β), and ER stress parameters.

Results

IPostC or/and TMZ significantly decreased cytolysis, oxidative stress and improved renal function in comparison to I/R group. IPostC but not TMZ significantly attenuated ER stress parameters versus I/R group. Indeed, it down-regulated the glucose-regulated protein 78 (GRP78), the activating transcription factor 4 (ATF4), the RNA activated protein kinase (PKR)-like ER kinas (PERK), the X box binding protein-1 (XBP-1) and the caspase12 protein levels. TMZ treatment significantly augmented GSK3-β phosphorylation and reduced levels of cytochrome c and VDAC phosphorylation in comparison to IPostC application. The combination of both treatments gave a synergetic effect. It significantly improved the survival rate, attenuated cytolysis, oxidative stress and improved renal function.

Conclusion

This study revealed that IPostC protects kidney from I/R injury by suppressing ER stress while the beneficial effects of TMZ are mediated by mitochondria protection. The combination of both treatments ameliorated functional recovery.

Keywords:
Kidney; Ischemia-reperfusion; Ischemic postconditioning; Trimetazidine; Endoplasmic reticulum stress; Mitochondria