title: Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway.
abstract: OBJECTIVE
  Tempol is a protective antioxidant against ischemic injury in many animal models. The molecular mechanisms are not well understood. Nuclear factor erythroid 2-related factor (Nrf2) is a master transcription factor during oxidative stress, which is enhanced by activation of protein kinase C (PKC) pathway. Another factor, tubular epithelial apoptosis, is mediated by activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, Akt) signaling pathway during renal ischemic injury. We tested the hypothesis that tempol activates PKC or PI3K/Akt/Nrf2 pathways to transcribe many genes that coordinate endogenous antioxidant defense.
  
  
  METHODS
  The right renal pedicle was clamped for 45 minutes and the left kidney was removed to study renal ischemia/reperfusion (I/R) injury in C57BL/6 mice. The response was assessed from serum parameters, renal morphology and renal expression of PKC, phosphorylated-PKC (p-PKC), Nrf2, heme oxygenase-1 (HO-1), Akt, phosphorylated-Akt (p-Akt), pro-caspase-3 and cleaved caspase-3 in groups of sham and I/R mice given vehicle, or tempol (50 or 100 mg/kg, intraperitoneal injection).
  
  
  RESULTS
  The serum malondialdehyde (MDA, marker of reactive oxygen species) doubled and the BUN and creatinine increased 5- to 10-fold after I/R injury. Tempol (50 or 100 mg/kg) prevented the increases in MDA but only tempol (50 mg/kg) lessened the increases in BUN and creatinine and moderated the acute tubular necrosis. I/R did not change expression of PKC or p-PKC but reduced renal expression of Nrf2, p-Akt, HO-1 and pro-caspase-3 and increased cleaved caspase-3. Tempol (50 mg/kg) prevented these changes produced by I/R whereas tempol (100 mg/kg) had lesser or inconsistent effects.
  
  
  CONCLUSIONS
  Tempol (50 mg/kg) prevents lipid peroxidation and attenuates renal damage after I/R injury. The beneficial pathway apparently is not dependent on upregulation or phosphorylation of PKC, at lower tempol doses, does implicate upregulation of Akt with expression of Nrf2 that could account for the increase in the antioxidant gene HO-1 and a reduction in the cleavage of the cellular damage marker pro-caspase-3.
authors.affiliation: Department of Physiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Gensheng
authors.initials: G
authors.lastname: Zhang
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.forename: Renjun
authors.initials: R
authors.lastname: Wang
authors.forename: Minze
authors.initials: M
authors.lastname: Xu
authors.forename: Huiping
authors.initials: H
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
authors.forename: Ruisheng
authors.initials: R
authors.lastname: Liu
authors.forename: En Yin
authors.initials: EY
authors.lastname: Lai
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013113:Spin Labels; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013113:Spin Labels; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; C001803:tempol