Aspasia Pefanis, Anjan K Bongoni, Jennifer L McRae, Evelyn J Salvaris, Nella Fisicaro, James M Murphy, Francesco L Ierino, Peter J Cowan
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Here, we used a mouse model of unilateral kidney IRI to assess whether the inhibition of RIPK1 or RIPK3 kinase activity reduces AKI and the progression to kidney fibrosis. Mice treated with the RIPK1 inhibitor Nec-1s, either before or after IR, showed reduced kidney injury at 24 hr compared with controls, whereas no protection was offered by the RIPK3 inhibitor GSK´872. In contrast, treatment with either inhibitor from days 3 to 9 post-IR reduced the degree of kidney fibrosis at day 28. These findings further support the role of necroptosis in IRI and provide important validation for the contribution of both RIPK1 and RIPK3 catalytic activities in the progression of kidney fibrosis. 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引用次数: 0
摘要
缺血再灌注损伤(IRI)是指器官的血液供应暂时减少,然后恢复。肾脏 IRI 是急性肾损伤的一种形式,通常会发展成肾脏纤维化。坏死是一种调节性坏死途径,与肾脏 IRI 有关。坏死细胞死亡涉及 RIPK1 和 RIPK3 激酶的招募以及终端效应物 MLKL 伪激酶的激活。磷酸化的 MLKL 通过质膜破裂导致细胞死亡,引发 "坏死性炎症"。由于 RIPK1 和 RIPK3 在该通路中的顶端作用,它们被认为与肾脏纤维化的发展有关。在这里,我们使用单侧肾脏IRI小鼠模型来评估抑制RIPK1或RIPK3激酶活性是否能减轻急性肾损伤和肾脏纤维化的进展。与对照组相比,RIPK1抑制剂Nec-1s在IR之前或之后治疗小鼠,24小时后肾损伤有所减轻,而RIPK3抑制剂GSK´872则没有提供保护。相反,在红外照射后第 3-9 天使用任一种抑制剂都能减轻第 28 天时肾脏纤维化的程度。这些发现进一步支持了坏死蛋白在 IRI 中的作用,并为 RIPK1 和 RIPK3 的催化活性在肾脏纤维化进程中的贡献提供了重要的验证。靶向坏死通路可能是减轻IR后肾脏疾病的一种有前途的治疗策略。
Inhibition of RIPK1 or RIPK3 kinase activity post ischemia-reperfusion reduces the development of chronic kidney injury.
Ischemia-reperfusion injury (IRI) occurs when the blood supply to an organ is temporarily reduced and then restored. Kidney IRI is a form of acute kidney injury (AKI), which often progresses to kidney fibrosis. Necroptosis is a regulated necrosis pathway that has been implicated in kidney IRI. Necroptotic cell death involves the recruitment of the RIPK1 and RIPK3 kinases and the activation of the terminal effector, the mixed lineage kinase domain-like (MLKL) pseudokinase. Phosphorylated MLKL causes cell death by plasma membrane rupture, driving 'necroinflammation'. Owing to their apical role in the pathway, RIPK1 and RIPK3 have been implicated in the development of kidney fibrosis. Here, we used a mouse model of unilateral kidney IRI to assess whether the inhibition of RIPK1 or RIPK3 kinase activity reduces AKI and the progression to kidney fibrosis. Mice treated with the RIPK1 inhibitor Nec-1s, either before or after IR, showed reduced kidney injury at 24 hr compared with controls, whereas no protection was offered by the RIPK3 inhibitor GSK´872. In contrast, treatment with either inhibitor from days 3 to 9 post-IR reduced the degree of kidney fibrosis at day 28. These findings further support the role of necroptosis in IRI and provide important validation for the contribution of both RIPK1 and RIPK3 catalytic activities in the progression of kidney fibrosis. Targeting the necroptosis pathway could be a promising therapeutic strategy to mitigate kidney disease following IR.
期刊介绍:
Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology.
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