title: Ischemic preconditioning reduces endoplasmic reticulum stress and upregulates hypoxia inducible factor-1α in ischemic kidney: the role of nitric oxide.
abstract: 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-1α (HIF-1α) 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-1α 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-1α 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.
  
  
  CONCLUSIONS
  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-1α stabilization. The beneficial impact of IPC was abolished when NO production is inhibited before IPC application.
authors.affiliation: Laboratory of human physiology, faculty of pharmacy, university of Monastir, Tunisia.
authors.forename: Asma
authors.initials: A
authors.lastname: Mahfoudh-Boussaid
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.forename: Kaouther
authors.initials: K
authors.lastname: Hadj-Ayed
authors.forename: Abdel-Hédi
authors.initials: AH
authors.lastname: Miled
authors.forename: Dalila
authors.initials: D
authors.lastname: Saidane-Mosbahi
authors.forename: Joan
authors.initials: J
authors.lastname: Rosello-Catafau
authors.forename: Hassen
authors.initials: H
authors.lastname: Ben Abdennebi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western / Q000662:veterinary; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007275:Injections, Intravenous / Q000662:veterinary; D019194:Ischemic Preconditioning / Q000662:veterinary*; D007668:Kidney / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000503:physiopathology / Q000662:veterinary*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D047992:TNF Receptor-Associated Factor 2; D019892:eIF-2 Kinase; C497110:Atf4 protein, rat; C051684:GRP78 protein, rat; C000717247:HSPA5 protein, human; C497444:Hif1a protein, rat; C496316:Nos3 protein, rat; C494920:Akt1 protein, rat