Identification of cell division cycle protein 20 in various forms of acute and chronic kidney injury in mice.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-08-01 DOI:10.1152/ajprenal.00302.2022
Mallory Swanson, Jiyoung Yun, Daniel M Collier, Connor Seif, Chao-Yie Yang, Kevin R Regner, Frank Park
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Abstract

Tubular epithelial cell fate following exposure to various types of injurious stimuli can be decided at distinct cell cycle checkpoints. One such checkpoint occurs during mitosis, known as the spindle assembly checkpoint, and is tightly regulated through the actions of cell division cycle protein 20 (CDC20). Due to our paucity of knowledge about the role of CDC20 in the kidney, the present study was designed to investigate the expression levels and distribution of CDC20 within the kidney and how pharmacological inhibition of CDC20 function affects kidney recovery using various rodent models of kidney injury. CDC20 is normally detected in distal tubules, but upon injury by either cisplatin administration or ureter obstruction, CDC20 accumulation is considerably elevated. Blockade of CDC20 activity using a selective pharmacological inhibitor, Apcin, lowered serum creatinine, tubular damage, and DNA injury following acute kidney injury compared with vehicle-treated mice. In unilateral ureteral obstruction, Apcin reduced tissue kidney injury molecule-1 levels, sirius red staining, and tubulointerstitial α-smooth muscle actin staining in the tissue. The findings in the present study demonstrated that elevations in CDC20 levels in the kidney are associated with kidney injury and that inhibition of CDC20 can alleviate and reverse some of the pathological effects on the architecture and function of kidney.NEW & NOTEWORTHY To our knowledge, this is the first study to characterize the expression and localization of cell division cycle 20 protein (CDC20) in normal and acute, and chronically injured kidneys. Tubular epithelial cell damage was markedly reduced through the administration of a selective inhibitor of CDC20, Apcin. This study provides new evidence that CDC20 can be induced in damaged kidney cells and negatively impact the recovery of the kidney following acute kidney injury.

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细胞分裂周期蛋白20在小鼠各种急慢性肾损伤中的表达。
暴露于各种类型的有害刺激后,小管上皮细胞的命运可以在不同的细胞周期检查点决定。一个这样的检查点发生在有丝分裂期间,被称为纺锤体组装检查点,并通过细胞分裂周期蛋白20 (CDC20)的作用受到严格调节。由于我们对CDC20在肾脏中的作用缺乏了解,本研究旨在研究CDC20在肾脏中的表达水平和分布,以及CDC20功能的药理抑制如何影响肾脏恢复。CDC20通常在远端小管中检测到,但在顺铂给药或输尿管梗阻损伤时,CDC20的积累明显升高。使用选择性药理抑制剂Apcin阻断CDC20活性,与药物处理小鼠相比,急性肾损伤后血清肌酐降低,小管损伤和DNA损伤。在单侧输尿管梗阻中,Apcin降低组织肾损伤分子-1水平、天狼星红染色和组织小管间质α-平滑肌肌动蛋白染色。本研究结果表明,肾脏中CDC20水平升高与肾损伤有关,抑制CDC20可以减轻和逆转一些对肾脏结构和功能的病理影响。据我们所知,这是第一个描述正常、急性和慢性损伤肾脏中细胞分裂周期20蛋白(CDC20)表达和定位的研究。通过给药CDC20选择性抑制剂Apcin,小管上皮细胞损伤明显减轻。本研究提供了新的证据,证明CDC20可以在受损的肾细胞中被诱导,并对急性肾损伤后肾脏的恢复产生负面影响。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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