Indirect podocyte injury manifested in a partial podocytectomy mouse model
Indirect podocyte injury manifested in a partial podocytectomy mouse model
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DOI：
10.1152/ajprenal.00602.2020
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发表时间：
2021-05-01
影响因子：
4.2
通讯作者：
Matsusaka, Taiji
中科院分区：
文献类型：
--
作者：
Okabe, Masahiro;Yamamoto, Kazuyoshi;Matsusaka, Taiji
在进行性肾小球疾病中，节段性足细胞损伤往往会扩大，导致全身性肾小球硬化，其机制尚不清楚。为了研究足细胞损伤的扩大，我们建立了一种新的嵌合小鼠模型，其中一部分足细胞表达人（h）CD25并且可以被免疫毒素LMB2损伤。 hCD25(+)和hCD25(-)足细胞被设计为分别表达tdTomato和增强型绿色荧光蛋白(EGFP)，这使得足细胞的细胞分选分析成为可能。注射LMB2后，嵌合小鼠出现蛋白尿和肾小球硬化。不仅是 tdTomato(+) 足细胞，而且 EGFP(+) 足细胞数量均减少并显示出损伤，这可以通过蛋白质和 RNA 水平上的去氧肾上腺素 (nephrin) 减少和结蛋白 (desmin) 增加来证明。转录组学分析发现，EGFP(+) 足细胞中糖皮质激素诱导的转录物 1 基因减少，血小板反应蛋白 4、肝素结合 EGF 样生长因子和转化生长因子-β 基因增加；这些基因可能是继发性足细胞损伤的候选介质。通路分析表明粘着斑、整合素介导的细胞粘着和雷帕霉素信号传导的粘着斑-磷脂酰肌醇3-激酶-Akt-哺乳动物靶标参与继发性足细胞损伤。最后，用血管紧张素 II 受体阻滞剂治疗嵌合小鼠可显着改善继发性足细胞损伤。这种马赛克足细胞损伤模型清楚地表明，受损的足细胞会导致继发性足细胞损伤，这可能是进行性肾脏疾病的一个有前途的治疗靶点。新的和值得注意的这种新颖的马赛克模型已经证明，当一小部分足细胞受伤时，其他足细胞也会受到继发性损伤。无论足细胞损伤的主要原因是什么，这种损伤的扩散可能普遍发生，导致终末期肾衰竭。了解继发性足细胞损伤的分子机制及其预防对于进展性肾脏疾病的治疗具有重要意义。该模型将成为研究间接足细胞损伤的有力工具。
In progressive glomerular diseases, segmental podocyte injury often expands, leading to global glomerulosclerosis by unclear mechanisms. To study the expansion of podocyte injury, we established a new mosaic mouse model in which a fraction of podocytes express human (h)CD25 and can be injured by the immunotoxin LMB2. hCD25(+) and hCD25(-) podocytes were designed to express tdTomato and enhanced green fluorescent protein (EGFP), respectively, which enabled cell sorting analysis of podocytes. After the injection of LMB2, mosaic mice developed proteinuria and glomerulosclerosis. Not only tdTomato(+) podocytes but also EGFP(+) podocytes were decreased in number and showed damage, as evidenced by a decrease in nephrin and an increase in desmin at both protein and RNA levels. Transcriptomics analysis found a decrease in the glucocorticoid-induced transcript 1 gene and an increase in the thrombospondin 4, heparin-binding EGF-like growth factor, and transforming growth factor-beta genes in EGFP(+) podocytes; these genes may be candidate mediators of secondary podocyte damage. Pathway analysis suggested that focal adhesion, integrin-mediated cell adhesion, and focal adhesion-phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin signaling are involved in secondary podocyte injury. Finally, treatment of mosaic mice with angiotensin II receptor blocker markedly ameliorated secondary podocyte injury. This mosaic podocyte injury model has distinctly demonstrated that damaged podocytes cause secondary podocyte damage, which may be a promising therapeutic target in progressive kidney diseases.NEW & NOTEWORTHY This novel mosaic model has demonstrated that when a fraction of podocytes is injured, other podocytes are subjected to secondary injury. This spreading of injury may occur ubiquitously irrespective of the primary cause of podocyte injury, leading to end-stage renal failure. Understanding the molecular mechanism of secondary podocyte injury and its prevention is important for the treatment of progressive kidney diseases. This model will be a powerful tool for studying the indirect podocyte injury.