- 作者: Asma Mahfoudh-Boussaid, Mohamed Amine MA Zaouali, Thierry Hauet, Kaouther Hadj-Ayed, Abdel-Hedi AH Miled, Sonia Ghoul-Mazgar, Dalila Saidane-Mosbahi, Joan Rosello-Catafau and Hassen Ben Abdennebi
- 作者服務機構: Laboratory of human physiology, faculty of pharmacy, university of Monastir, Monastir, Tunisia
- 中文摘要: --
- 英文摘要:
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. - 中文關鍵字: --
- 英文關鍵字: Kidney, Ischemia-reperfusion, Ischemic postconditioning, Trimetazidine, Endoplasmic reticulum stress, Mitochondria