Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
Biotechnology Center, Technische Universität Dresden, 01307, Dresden, Germany.
Cell Death Dis. 2022 Mar 14;13(3):236. doi: 10.1038/s41419-022-04682-3.
The cytosolic protein rubicon (RUBCN) has been implicated in the removal of necrotic debris and autoimmunity. However, the role of RUBCN in models of acute kidney injury (AKI), a condition that typically involves necrotic kidney tubules, was not investigated. Here, we demonstrate that RUBCN-deficient mice are hypersensitive to renal damage induced by ischemia-reperfusion injury (IRI) and cisplatin-induced AKI. Combined deficiency of RUBCN and mixed lineage kinase domain-like (MLKL) partially reversed the sensitivity in the IRI model suggesting that the absence of RUBCN sensitizes to necroptosis in that model. Necroptosis is known to contribute to TNFα-induced severe inflammatory response syndrome (SIRS), but we detected no statistically significant difference in overall survival following injection of TNFα in RUBCN-deficient mice. We additionally generated RUBCN-deficient mice which lack gasdermin D (GSDMD), the terminal mediator of pyroptosis, but no reversal of the AKI phenotype was observed. Finally, and in contrast to the previous understanding of the role of RUBCN, we did not find a significant autoimmune phenotype in RUBCN-deficient mice, but detected chronic kidney injury (CKD) in aged RUBCN-deficient mice of both sexes. In summary, our data indicate that RUBCN-deficient mice are hypersensitive to kidney injury.
细胞质蛋白 rubicon（RUBCN）已被牵涉到清除坏死细胞碎片和自身免疫中。然而，RUBCN 在急性肾损伤（AKI）模型中的作用，通常涉及坏死的肾小管，尚未被研究。在这里，我们证明 RUBCN 缺陷小鼠对缺血再灌注损伤（IRI）和顺铂诱导的 AKI 诱导的肾损伤敏感。RUBCN 和混合谱系激酶结构域样（MLKL）的联合缺乏部分逆转了 IRI 模型中的敏感性，表明 RUBCN 的缺乏使该模型中的坏死细胞凋亡敏感。坏死细胞凋亡已知会导致 TNFα 诱导的严重炎症反应综合征（SIRS），但我们在 RUBCN 缺陷小鼠中注射 TNFα 后没有检测到总生存率的统计学显著差异。我们还生成了缺乏天冬氨酸半胱氨酸特异性蛋白酶 1（caspase-1）的 RUBCN 缺陷小鼠，其缺乏细胞焦亡的终端介体 gasdermin D（GSDMD），但未观察到 AKI 表型的逆转。最后，与以前对 RUBCN 作用的理解相反，我们在 RUBCN 缺陷小鼠中没有发现明显的自身免疫表型，但在 RUBCN 缺陷的雄性和雌性老年小鼠中检测到慢性肾脏损伤（CKD）。总之，我们的数据表明 RUBCN 缺陷小鼠对肾损伤敏感。
