Kaouther Hadj-Ayed, Asma Mahfoudh-Boussaid, Dalila Saidane-Mosbahi, Joan Roselló-Catafau, Mohamed Amine Zaouali, Sonia Ghoul-Mazgar, Abdelhedi Miled, Thierry Hauet, Hassen Ben Abdennebi, Laboratory of human physiology, Faculty of Pharmacy-Université de Monastir - University of Monastir (UM), Department of experimental pathology, Hepatic ischemia reperfusion unit-Institute of Biomedical Research of Barcelona of the Spanish National Research Council (IIBB-CSIC), Ischémie - Reperfusion en transplatation rénale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Laboratory of biochemistry, Université de Monastir - University of Monastir (UM)-Faculty of Pharmacy, Laboratory of histology and embryology, Université de Monastir - University of Monastir (UM)-faculty of dental medicine, This work was supported by the Tunisian Ministry of Higher Education and Scientific Research and The Spanish Ministry of Foreign Affairs and Cooperation/ AECID (A/031197/10)., and BMC, Ed.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al., [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., This work was supported by the Tunisian Ministry of Higher Education and Scientific Research and The Spanish Ministry of Foreign Affairs and Cooperation/ AECID (A/031197/10).