PMID- 22252226 OWN - NLM STAT- MEDLINE DCOM- 20120516 LR - 20220410 IS - 1423-0127 (Electronic) IS - 1021-7770 (Print) IS - 1021-7770 (Linking) VI - 19 IP - 1 DP - 2012 Jan 17 TI - Ischemic preconditioning reduces endoplasmic reticulum stress and upregulates hypoxia inducible factor-1alpha in ischemic kidney: the role of nitric oxide. PG - 7 LID - 10.1186/1423-0127-19-7 [doi] AB - 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-1alpha (HIF-1alpha) 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 NG-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-1alpha 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. Parallelly, IPC enhanced Akt phosphorylation, eNOS, nitrite/nitrate and HIF-1alpha 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-1alpha stabilization. The beneficial impact of IPC was abolished when NO production is inhibited before IPC application. FAU - Mahfoudh-Boussaid, Asma AU - Mahfoudh-Boussaid A AD - Laboratory of human physiology, faculty of pharmacy, university of Monastir, Tunisia. FAU - Zaouali, Mohamed Amine AU - Zaouali MA FAU - Hadj-Ayed, Kaouther AU - Hadj-Ayed K FAU - Miled, Abdel-Hedi AU - Miled AH FAU - Saidane-Mosbahi, Dalila AU - Saidane-Mosbahi D FAU - Rosello-Catafau, Joan AU - Rosello-Catafau J FAU - Ben Abdennebi, Hassen AU - Ben Abdennebi H LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120117 PL - England TA - J Biomed Sci JT - Journal of biomedical science JID - 9421567 RN - 0 (Atf4 protein, rat) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (GRP78 protein, rat) RN - 0 (HSPA5 protein, human) RN - 0 (Heat-Shock Proteins) RN - 0 (Hif1a protein, rat) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (TNF Receptor-Associated Factor 2) RN - 145891-90-3 (Activating Transcription Factor 4) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, rat) RN - EC 2.7.11.1 (Akt1 protein, rat) RN - EC 2.7.11.1 (PERK kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (eIF-2 Kinase) RN - V55S2QJN2X (NG-Nitroarginine Methyl Ester) SB - IM MH - Activating Transcription Factor 4/metabolism MH - Animals MH - Blotting, Western/veterinary MH - Endoplasmic Reticulum Chaperone BiP MH - *Endoplasmic Reticulum Stress MH - Heat-Shock Proteins/metabolism MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism MH - Injections, Intravenous/veterinary MH - Ischemic Preconditioning/*veterinary MH - Kidney/physiopathology MH - Male MH - NG-Nitroarginine Methyl Ester/pharmacology MH - Nitric Oxide/*metabolism MH - Nitric Oxide Synthase Type III/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Rats, Wistar MH - Reperfusion Injury/physiopathology/*veterinary MH - TNF Receptor-Associated Factor 2/metabolism MH - Up-Regulation MH - eIF-2 Kinase/metabolism PMC - PMC3398272 EDAT- 2012/01/19 06:00 MHDA- 2012/05/17 06:00 PMCR- 2012/01/17 CRDT- 2012/01/19 06:00 PHST- 2011/11/03 00:00 [received] PHST- 2012/01/17 00:00 [accepted] PHST- 2012/01/19 06:00 [entrez] PHST- 2012/01/19 06:00 [pubmed] PHST- 2012/05/17 06:00 [medline] PHST- 2012/01/17 00:00 [pmc-release] AID - 1423-0127-19-7 [pii] AID - 10.1186/1423-0127-19-7 [doi] PST - epublish SO - J Biomed Sci. 2012 Jan 17;19(1):7. doi: 10.1186/1423-0127-19-7.