Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway.
Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway.
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Tempol通过PI 3 K/Akt/Nrf 2信号通路对急性肾损伤的保护作用
DOI：
10.1159/000443414
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发表时间：
2016
影响因子：
2.8
通讯作者：
Lai EY
中科院分区：
文献类型：
--
作者：
Zhang G;Wang Q;Zhou Q;Wang R;Xu M;Wang H;Wang L;Wilcox CS;Liu R;Lai EY
Tempol在许多动物模型中是抗缺血性损伤的保护性抗氧化剂。其分子机制还不清楚。核因子红细胞2相关因子（Nrf 2）是氧化应激过程中的主要转录因子，通过激活蛋白激酶C（PKC）途径而增强。另一个因素，肾小管上皮细胞凋亡，在肾缺血损伤期间通过激活磷酸肌醇3-激酶（PI 3 K）/蛋白激酶B（PKB，Akt）信号通路介导。我们测试了tempol激活PKC或PI 3 K/Akt/Nrf 2通路来转录许多协调内源性抗氧化防御的基因的假设。在C57 BL/6小鼠中，将右肾蒂夹闭45分钟，并移除左肾以研究肾缺血/再灌注（I/R）损伤。在给予溶剂或tempol（50或100 mg/kg，腹膜内注射）的假手术和I/R小鼠组中，从血清参数、肾脏形态学和PKC、磷酸化PKC（p-PKC）、Nrf 2、血红素加氧酶-1（HO-1）、Akt、磷酸化Akt（p-Akt）、半胱天冬酶原-3和裂解半胱天冬酶-3的肾脏表达评估反应。I/R损伤后，血清丙二醛（MDA，活性氧的标志物）加倍，BUN和肌酐升高5- 10倍。Tempol（50或100 mg/kg）可抑制MDA的升高，但仅Tempol（50 mg/kg）可减轻BUN和肌酐的升高，并减轻急性肾小管坏死。I/R不改变PKC或p-PKC的表达，但降低肾Nrf 2、p-Akt、HO-1和caspase-3原的表达，并增加切割的caspase-3。Tempol（50 mg/kg）阻止了I/R产生的这些变化，而Tempol（100 mg/kg）的作用较小或不一致。Tempol（50 mg/kg）可预防I/R损伤后的脂质过氧化反应并减轻肾损伤。有益途径显然不依赖于PKC的上调或磷酸化，在较低的tempol剂量下，确实涉及Akt的上调和Nrf 2的表达，这可以解释抗氧化剂基因HO-1的增加和细胞损伤标记物caspase-3原的切割的减少。
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. 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). 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. 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.