A Novel VCP modulator KUS121 exerts renoprotective effects in ischemia-reperfusion injury with retaining ATP and restoring ERAD-processing capacity.
A Novel VCP modulator KUS121 exerts renoprotective effects in ischemia-reperfusion injury with retaining ATP and restoring ERAD-processing capacity.
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新型 VCP 调节剂 KUS121 通过保留 ATP 和恢复 ERAD 处理能力，在缺血再灌注损伤中发挥肾脏保护作用。
DOI：
10.1152/ajprenal.00392.2021
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发表时间：
2022
影响因子：
4.2
通讯作者：
Kuwabara Takashige
中科院分区：
文献类型：
--
作者：
Hata Yusuke;Date Ryosuke;Fujimoto Daisuke;Ikeda Hanako Ohashi;Umemoto Shuro;Kanki Tomoko;Nishiguchi Yoshihiko;Mizumoto Teruhiko;Hayata Manabu;Kakizoe Yutaka;Izumi Yuichiro;Kakizuka Akira;Mukoyama Masashi;Kuwabara Takashige
急性肾损伤（阿基）是一种危及生命的疾病，即使在恢复后也经常进展为慢性肾脏疾病或其他器官功能障碍。尽管阿基在全球范围内的认知度提高，患病率也很高，但迄今为止还没有确定的治疗方法。本研究的目的是研究京都大学物质121（KUS 121），一种新的含缬沙素的蛋白质调节剂，对阿基的肾保护作用。在体外实验中，我们评估了内质网（ER）应激条件下有或无KUS 121的近端肾小管细胞的细胞活力和ATP水平。在体内实验中，检查了KUS 121对缺血-再灌注损伤引起的阿基小鼠的作用。ER相关降解（ERAD）处理能力通过ERAD底物CD 3 δ-YFP的定量进行评价。KUS 121保护近端肾小管细胞免于ER应激下的细胞死亡。如通过抑制C/EBP同源蛋白表达和半胱天冬酶-3切割所指示的，通过KUS 121给药维持细胞内ATP水平，细胞凋亡反应减轻。KUS 121治疗抑制了血清肌酐和中性粒细胞明胶酶相关脂质运载蛋白水平的升高，并减轻了缺血再灌注后的肾小管损伤。在KUS 121治疗组中，肾脏中炎性细胞因子的表达也受到抑制。在体外和体内，KUS 121均未改变含Valosin的蛋白表达水平。KUS 121处理恢复了ERAD处理能力，这与其上游途径、磷酸化肌醇需要酶-1 α和剪接的X盒结合蛋白-1的增强有关。结论：KUS 121具有保护肾小管细胞免受内质网应激损伤的作用，提示KUS 121有可能成为一种新型的治疗缺血相关阿基的药物。本研究的新发现如下：1）京都大学物质121（KUS 121），一种新型的含缬氨肽蛋白（valosin-containing protein，VCP）调节剂，可以减少VCP对ATP的消耗; 2）KUS 121可减轻近端肾小管上皮细胞内质网应激，提高细胞活力;3）KUS 121对缺血再灌注损伤有保护作用; KUS 121可预防缺血性急性肾损伤，并可恢复ER相关的降解能力。
Acute kidney injury (AKI) is a life-threatening condition and often progresses to chronic kidney disease or the development of other organ dysfunction even after recovery. Despite the increased recognition and high prevalence of AKI worldwide, there has been no established treatment so far. The aim of this study was to investigate the renoprotective effect of Kyoto University substance 121 (KUS121), a novel valosin-containing protein modulator, on AKI. In in vitro experiments, we evaluated cell viability and ATP levels of proximal tubular cells with or without KUS121 under endoplasmic reticulum (ER) stress conditions. In in vivo experiments, the effects of KUS121 were examined in mice with AKI caused by ischemia-reperfusion injury. ER-associated degradation (ERAD)-processing capacity was evaluated by quantification of the ERAD substrate CD3delta-YFP. KUS121 protected proximal tubular cells from cell death under ER stress. The apoptotic response was mitigated as indicated by the suppression of C/EBP homologous protein expression and caspase-3 cleavage, with maintained intracellular ATP levels by KUS121 administration. KUS121 treatment suppressed the elevation of serum creatinine and neutrophil gelatinase-associated lipocalin levels and attenuated renal tubular damage after ischemia-reperfusion. The expression of inflammatory cytokines in the kidney was also suppressed in the KUS121-treated group. Valosin-containing protein expression levels were not altered by KUS121 both in vitro and in vivo. KUS121 treatment restored ERAD-processing capacity associated with potentiation of its upstream pathway, phosphorylated inositol-requiring enzyme-1α, and spliced X box-binding protein-1. In conclusion, these findings indicate that KUS121 can protect renal tubular cells from ER stress-induced injury, suggesting that KUS121 could be a novel and promising therapeutic compound for ischemia-associated AKI.NEW & NOTEWORTHYNovel findings of this study are as follows:1) Kyoto University substance 121 (KUS121), a novel valosin-containing protein (VCP) modulator, can reduce ATP consumption of VCP;2) KUS121 reduced endoplasmic reticulum (ER) stress and improved cell viability in proximal tubular cells;3) KUS121 exerted renoprotective effects against ischemia-reperfusion injury; and4) KUS121 may prevent ischemic acute kidney injury with ATP retention and restoring ER-associated degradation capacity.
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DOI：
--
发表时间：
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期刊：
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DOI：
--
发表时间：
2014
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AJP - Renal Physiology
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DOI：
10.1152/ajprenal.00691.2016
发表时间：
2018
期刊：
American journal of physiology. Renal physiology
影响因子：
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作者：
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通讯作者：
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影响因子：
8.2
作者：
Kuwabara, T.;Mori, K.;Nakao, K.
通讯作者：
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