Role of gap junction-mediated intercellular communication on schaemia/reperfusion renal injury

间隙连接介导的细胞间通讯在缺血/再灌注肾损伤中的作用

• 批准号: 23591187
• 负责人: YAO Jian
• 金额: $ 3.33万
• 依托单位: University of Yamanashi
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591187/
• 关键词: 病理学; 腎臓; 虚血; 細胞死; ギャップ結合; 酸化ストレス; AMPK; ATP; コネキシン43; ヘミチャネル; 炎症; connexin43

Connexin-forming channels regulates cell survival with little information available regarding its mechanisms. Using a ischemic renal injury model, we explored the potential mechanisms of Cx43-forming channels on renal cell survival. Our results showed that Cx43 influenced cell susceptibility to ischemic renal injury. Cells with higher level of Cx43 were more vulnerable to ischemic oxidative injury. On the contrary, cells with no or lower level of Cx43 were resistant. Further analysis revealed that oxidative stimuli activated Cx43 hemichannels, leading to extracellular loss of ATP. The released ATP, in turn, suppressed AMPK activation through purinergistic receptor-mediated activation of AKT and mTOR. Suppression of hemichannels enhanced AMPK activation, thus protecting cells from oxidative injury. Our study indicates that Cx43 hemichannels determines cell susceptibility to oxidative injury. Targeting Cx43 could be developed for prevention and treatment of ischemic renal injury.

连接蛋白形成通道调节细胞存活，但对其机制知之甚少。利用缺血肾损伤模型，我们探讨了Cx43形成通道对肾细胞存活的潜在机制。我们的结果表明，Cx43影响细胞对缺血性肾损伤的敏感性。Cx43水平高的细胞更容易受到缺血性氧化损伤的影响。相反，不表达或低水平表达Cx43的细胞为耐药细胞。进一步的分析表明，氧化刺激激活了Cx43半通道，导致细胞外ATP的丢失。释放的ATP反过来通过嘌呤受体介导的AKT和mTOR激活来抑制AMPK的激活。抑制半角蛋白能增强AMPK的激活，从而保护细胞免受氧化损伤。我们的研究表明，Cx43半通道决定了细胞对氧化损伤的敏感性。靶向Cx43可用于预防和治疗缺血性肾损伤。

项目成果

Phenotypic shift of activated glomerular cells towards redifferentiation by the unfolded protein response

通过未折叠的蛋白质反应，活化的肾小球细胞向再分化的表型转变

• 作者: Johno H;et al.
• 通讯作者: et al.

Dysfunction of gap junctions stimulates COX-2 expression in juxtaglomerular renin-secreting cells

间隙连接功能障碍刺激肾小球旁肾素分泌细胞中COX-2的表达

• 发表时间: 2011
• 作者: Yao J;Zhu Y;and Kitamura M
• 通讯作者: and Kitamura M

Suppression of inflammatory cytokines-triggered NFκB activation and iNOS expression in renal tubular cells by gap junction inhibitor flufenamic acid: a critical involvement of AMPK

间隙连接抑制剂氟芬那酸抑制肾小管细胞中炎症细胞因子触发的 NFκB 激活和 iNOS 表达：AMPK 的关键参与

• 作者: Chi Y;et al.
• 通讯作者: et al.

Cytoprotective roles of ERK and Akt in endoplasmic reticulum stress triggered by subtilase cytotoxin.

• DOI: 10.1016/j.bbrc.2011.06.078
• 发表时间: 2011-07
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Tian Tian-Tian;Yang Zhao;S. Nakajima;Tao Huang;Jian Yao;A. Paton;J. Paton;M. Kitamura

Purinergic control of AMPK activation by ATP released through connexin43 hemichannels : pivotal roles in hemichannel-mediated disassembly of tight junction and cell injury

通过连接蛋白43半通道释放的ATP对AMPK激活的嘌呤能控制：在半通道介导的紧密连接解体和细胞损伤中的关键作用

• 发表时间: 2013
• 作者: Masaki Naito;et al.;Yao J
• 通讯作者: Yao J