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

Abstract

BackgroundEndoplasmic 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.MethodsKidneys 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.ResultsIPostC 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.ConclusionThis 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.

Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury

“…43 Additional research reported that early ischemic PC attenuated ER stress in ischemic kidneys via increasing the relative amounts of GRP78 and decreasing PERK, ATF4 and TNF-receptor associated factor 2 (TRAF2) levels. The beneficial impact of early ischemic PC was dependent on nitric oxide (NO) levels, as the protective effect was abolished when NO production was inhibited before early ischemic PC application.…”

Impact of propofol on renal ischemia/reperfusion endoplasmic reticulum stress

“…Knocking out the CHOP gene was shown to significantly reduce renal I/R injury in mice, and improve renal microcirculation after I/R 2 . Furthermore, post-ischemic preconditioning was shown to reduce the I/R-induced renal endoplasmic reticulum stress by downregulating the protein expression of glucose regulating protein 78 (GRP78), activating transcriptional factor 4 (ATF4), double-stranded RNA-dependent protein kinase-like ER kinase (PERK) protein, X box binding protein 1 (XBP-1), and caspase-12, thus alleviating renal I/R injury 14 . Therefore, if endoplasmic reticulum stress could be subdued, renal I/R injury could in turn be reduced.…”

Involvement of AMP-activated protein kinase in the protective effectof melatonin against renal ischemia reperfusion injury

“…), and the body temperature was maintained at 36-38 °C by placing the rats on a thermal blanket. Animals were submitted to a midline laparotomy, and ischemia was induced by bilateral renal pedicle clamping for 60 min (with the exception of the sham group) with smooth vascular clamps, as previously described (Mahfoudh Boussaid et al, 2012). After the clamps were released, the incisions were closed by running suture, and rats were allowed to recover and kept warm.…”

“…As previously described by Mahfoudh Boussaid et al (2012), renal function was assessed in terms of creatinine clearance calculated using the following formula:…”