The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway
The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway
复制标题
过氧化物酶体增殖物激活受体 γ 激动剂吡格列酮通过 AMPK-SIRT1/p300 途径减少 p65 乙酰化，从而防止顺铂肾毒性中 NF-kappaB 的激活。
DOI：
10.1016/j.bcp.2015.11.027
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发表时间：
2016-02-01
影响因子：
5.8
通讯作者：
Xu, Gang
中科院分区：
文献类型：
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作者：
Zhang, Jiong;Zhang, Ying;Xu, Gang
噻唑烷二酮吡格列酮也是一种PPAR-γ激动剂，目前广泛用于高胆固醇血症和高胆固醇血症患者。NF-κ B是一种广泛表达的转录因子，控制炎症中涉及的许多基因的表达。本研究的目的是评价在顺铂肾毒性中，PPAR-gamma的激活是否减弱顺铂诱导的NF-κ B激活。结果显示，PPAR-γ激动剂吡格列酮降低NF-κ B p65转录靶基因的表达（例如，IL-6、IL-1 β和TNF-α），并抑制顺铂肾毒性中的组织学损伤和炎性细胞浸润。吡格列酮处理后NF-κ B活性的抑制抑制了顺铂诱导的I κ B-α降解和NF-κ B p65亚基易位。NF-κ B B p65亚基的转运依赖于p65乙酰化，其主要由SIRT 1或p300调节。值得注意的是，AMP激酶（AMPK）激活不仅降低了p300的磷酸化、激活和p65相互作用，而且增加了SIRT 1表达、激活和p65结合，从而导致p65乙酰化的显著降低。有趣的是，在用PPAR-gamma拮抗剂GW 9662治疗后，顺铂肾毒性中吡格列酮治疗后IL-6、TNF-α和IL-1 β的减少、组织损伤的抑制和炎性细胞浸润减弱。这些结果表明，PPAR-gamma激动剂吡格列酮通过AMPK-SIRT 1/p300途径减少p65乙酰化，从而防止顺铂肾毒性中NF-κ B活化。(C)2015 Elsevier Inc. All rights reserved.
The thiazolidinedione pioglitazone, which is also a PPAR-gamma agonist, now is widely used in patients with hypercholesterolemia and hypertriglyceridemia. NF-kappa B is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. The aim of the present study was to evaluate whether the activation of PPAR-gamma attenuates the cisplatin-induced NF-kappa B activation in cisplatin nephrotoxicity. The results showed that the PPAR-gamma agonist pioglitazone decreased the expression of NF-kappa B p65 transcription target genes (e.g., IL-6, IL-1 beta, and TNF-alpha) and inhibited histological injury and inflammatory cells infiltration in cisplatin nephrotoxicity. The suppression of NF-kappa B activity following pioglitazone treatment inhibited the cisplatin-induced I kappa B-alpha degredation and NF-kappa B p65 subunit translocation. Translocation of the NF-kappa B p65 subunit depends on p65 acetylation, which primarily regulated by SIRT1 or p300. Notably, AMP kinase (AMPK) activation not only decreased the phosphorylation, activation and p65 interaction of p300 but also increased SIRT1 expression, activation and p65 binding, thus leading to a significant reduction in p65 acetylation. Interestingly, the reduction of IL-6, TNF-alpha and IL-1 beta, the inhibition of histological injury and the inflammatory cells infiltration following pioglitazone treatment in cisplatin nephrotoxicity were attenuated after treatment with the PPAR-gamma antagonist GW9662. These results suggest that the PPAR-gamma agonist pioglitazone prevents NF-kappa B activation in cisplatin nephrotoxicity through a reduction in p65 acetylation via the AMPK-SIRT1/p300 pathway. (C) 2015 Elsevier Inc. All rights reserved.