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Ischemic preconditioning reduces endoplasmic reticulum stress and upregulates hypoxia inducible factor-1α in ischemic kidney: the role of nitric oxide.

AbstractBACKGROUND:
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.
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-1α stabilization. The beneficial impact of IPC was abolished when NO production is inhibited before IPC application.
AuthorsAsma Mahfoudh-Boussaid, Mohamed Amine Zaouali, Kaouther Hadj-Ayed, Abdel-Hédi Miled, Dalila Saidane-Mosbahi, Joan Rosello-Catafau, Hassen Ben Abdennebi
JournalJournal of biomedical science (J Biomed Sci) Vol. 19 Pg. 7 (Jan 17 2012) ISSN: 1423-0127 [Electronic] England
PMID22252226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Atf4 protein, rat
  • Endoplasmic Reticulum Chaperone BiP
  • GRP78 protein, rat
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • TNF Receptor-Associated Factor 2
  • Activating Transcription Factor 4
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Akt1 protein, rat
  • PERK kinase
  • Proto-Oncogene Proteins c-akt
  • eIF-2 Kinase
  • NG-Nitroarginine Methyl Ester
Topics
  • Activating Transcription Factor 4 (metabolism)
  • Animals
  • Blotting, Western (veterinary)
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress
  • Heat-Shock Proteins (metabolism)
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Injections, Intravenous (veterinary)
  • Ischemic Preconditioning (veterinary)
  • Kidney (physiopathology)
  • Male
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Nitric Oxide (metabolism)
  • Nitric Oxide Synthase Type III (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rats
  • Rats, Wistar
  • Reperfusion Injury (physiopathology, veterinary)
  • TNF Receptor-Associated Factor 2 (metabolism)
  • Up-Regulation
  • eIF-2 Kinase (metabolism)

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