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[Background/aim] The aim of this study was to compare the effects of single and repeated trimetazidine (TMZ) administration against warm hepatic ischemia/reperfusion (I/R) injury and to explore the possible mechanisms affected by TMZ. [Materials and methods] Wistar rats were divided into 4 groups (n = 6). Sham: rats were subjected to dissection. I/R: rats were subjected to 60 min of partial hepatic ischemia followed by 24 h of reperfusion. TMZ1: Same as I/R group but rats were pretreated with a single dose of TMZ (10 mg/kg, intraperitoneal injection) 30 min before warm ischemia. TMZ3: Same as I/R but rats were treated with 10 mg/ kg TMZ for 3 successive days. [Results] TMZ treatment decreased liver injury, lipid peroxidation, and apoptosis. The repeated administration of TMZ conferred more protection than the single dose treatment concerning all studied parameters. In parallel, we noted a significant increase in phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) and endothelial nitric oxide synthase (eNOS) levels in TMZ3 as compared to TMZ1. [Conclusion] Repeated administration of TMZ for 3 days was more efficient than a single dose of TMZ in protecting the liver against I/R induced apoptosis and lipid peroxidation. These effects implicate AMPK and eNOS activation., This study was funded by the Tunisian Ministry of Higher Education and Scientific Research.

Melatonin (Mel) is widely used to attenuate ischemia/reperfusion (I/R) injury in several organs. Nevertheless, the underlying mechanisms remain unclear. This study was conducted to explore the effect of Mel on endoplasmic reticulum (ER) stress, Akt and MAPK cascades after renal warm I/R. Eighteen Wistar rats were randomized into three groups: Sham, I/R, and Mel + I/R. The ischemia period was 60 min followed by 120 min of reperfusion. Mel (10 mg/kg) was administrated 30 min prior to ischemia. The creatinine clearance, MDA, LDH levels, and histopathological changes were evaluated. In addition, Western blot was performed to study ER stress and its downstream apoptosis as well as phosphorylation of Akt, GSK-3β, VDAC, ERK, and P38. Mel decreased cytolysis and lipid peroxidation and improved renal function and morphology compared to I/R group. Parallely, it significantly reduced the ER stress parameters including GRP 78, p-PERK, XBP 1, ATF 6, CHOP, and JNK. Simultaneously, p-Akt level was significantly enhanced and its target molecules GSK-3βand VDAC were inhibited. Furthermore, the ERK and P38 phosphorylation were evidently augmented after Mel administration in comparison to I/R group. In conclusion, Mel improves the recovery of renal function by decreasing ER stress and stimulating Akt pathway after renal I/R injury.

© 2014 Informa Healthcare USA, Inc. All rights reserved. Renal ischemia reperfusion (I/R) injury, which occurs during renal surgery or transplantation, is the major cause of acute renal failure. Trimetazidine (TMZ), an anti-ischemic drug, protects kidney against the deleterious effects of I/R. However its protective mechanism remains unclear. The aim of this study is to examine the relevance of Akt, endothelial nitric oxide synthase (eNOS), and hypoxia inducible factor-1α (HIF-1α) on TMZ induced protection of kidneys against I/R injury. Wistar rats were subjected to 60 min of warm renal ischemia followed by 120 min of reperfusion, or to intraperitoneal injection of TMZ (3 mg/kg) 30 min before ischemia. In sham operated group renal pedicles were only dissected. Compared to I/R, TMZ treatment decreased lactate dehydrogenase (845 ± 13 vs. 1028 ± 30 U/L). In addition, creatinine clearance and sodium reabsorption rates reached 105 ± 12 versus 31 ± 11 μL/min/g kidney weight and 95 ± 1 versus 68 ± 5%, respectively. Besides, we noted a decrease in malondialdehyde concentration (0.33 ± 0.01 vs. 0.59 ± 0.03 nmol/mg of protein) and an increase in glutathione concentration (2.6 ± 0.2 vs. 0.93 ± 0.16 μg GSH/mg of protein), glutathione peroxidase (95 ± 4 vs. 61 ± 3 μg GSH/min/mg of protein), and superoxide dismutase (25 ± 3 vs. 11 ± 2 U/mg of protein) and catalase (91 ± 12 vs. 38 ± 9 μmol/min/mg of protein) activities. Parallely, we noted a significant increase in p-Akt, eNOS, nitrite and nitrate (18 ± 2 vs. 8 ± 0.1 pomL/mg of protein), HIF-1α (333 ± 48 vs. 177 ± 14 μg/mg of protein) and heme oxygenase-1 (HO-1) levels regarding I/R. TMZ treatment improves renal tolerance to warm I/R. Such protection implicates an activation of Akt/eNOS signaling pathway, HIF-1α stabilization and HO-1 activation.

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).

To present the results of ischaemic preconditioning (IPC), pharmacological preconditioning with vitamin C (Vit C) and a combination of the two modalities on functional recovery of rat kidneys after prolonged warm ischaemia.Forty six rats were divided into 5 experimental groups. Kidneys of the sham group (n = 9) were only submitted to dissection of the pedicle. Ischaemia (60 min, n = 10) was induced by clamping both kidneys. IPC (n = 9) consisted of two successive cycles (5 min/5 min) of ischaemia/reperfusion (I/R). Vit C (100 mg/Kg, n = 9) was administered by intravenous injection 30 min before warm ischaemia. The Vit C + IPC (n= 9) group received the combination of both treatments. Tissue malonedialdehyde (MDA), plasma lactate dehydrogenase (LDH), tubular reabsorption of sodium (TRNa) and creatinine clearance (GFR) were evaluated after 120 min of kidney reperfusion.Ischaemic kidneys showed a significant increase of MDA and LDH concentrations and a significant reduction of GFR and TRNa compared to the sham group. The use of lPC or Fit C induced a significant improvement of renal function compared to the ischaemia group. The combination of Vit C + IPC induced a slight improvement of experimental parameters compared to those of the ischaemia group, but did not improve kidney functioning compared to the use of either IPC or Vit C alone.IPC and Fit C improve the functional parameters of ischaemic kidneys. However the protective effects are attenuated when the two treatments are combined.

Background: Although recent studies indicate that renal ischemic preconditioning (IPC) protects the kidney from ischemia-reperfusion (I/R) injury, the precise protective mechanism remains unclear. In the current study, we investigated whether early IPC could upregulate hypoxia inducible transcription factor-1 (HIF-1) expression and could reduce endoplasmic reticulum (ER) stress after renal I/R and whether pharmacological inhibition of nitric oxide (NO) production would abolish these protective effects. Methods. Kidneys of Wistar rats were subjected to 60 min of warm ischemia followed by 120 min of reperfusion (I/R group), or to 2 preceding cycles of 5 min ischemia and 5 min reperfusion (IPC group), or to intravenously injection of N G-nitro-L- arginine methylester (L-NAME, 5 mg/kg) 5 min before IPC (L-NAME+IPC group). The results of these experimental groups were compared to those of a sham-operated group. Sodium reabsorption rate, creatinine clearance, plasma lactate dehydrogenase (LDH) activity, tissues concentrations of malonedialdehyde (MDA), HIF-1 and nitrite/nitrate were determined. In addition, Western blot analyses were performed to identify the amounts of Akt, endothelial nitric oxide synthase (eNOS) and ER stress parameters. Results: IPC decreased cytolysis, lipid peroxidation and improved renal function. Parallely, IPC enhanced Akt phosphorylation, eNOS, nitrite/nitrate and HIF-1 levels as compared to I/R group. Moreover, our results showed that IPC increased the relative amounts of glucose-regulated protein 78 (GRP78) and decreased those of RNA activated protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 4 (ATF4) and TNF-receptor-associated factor 2 (TRAF2) as judged to I/R group. However, pre treatment with L-NAME abolished these beneficial effects of IPC against renal I/R insults. Conclusion: These findings suggest that early IPC protects kidney against renal I/R injury via reducing oxidative and ER stresses. These effects are associated with phosphorylation of Akt, eNOS activation and NO production contributing thus to HIF-1 stabilization. The beneficial impact of IPC was abolished when NO production is inhibited before IPC application. © 2012 Mahfoudh-Boussaid et al; licensee BioMed Central Ltd., 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).