A novel renal carbonic anhydrase type III plays a role in proximal tubule dysfunction
A novel renal carbonic anhydrase type III plays a role in proximal tubule dysfunction
复制标题
DOI：
10.1038/sj.ki.5002794
复制
发表时间：
2008-07-01
影响因子：
19.6
通讯作者：
Devuyst, O.
中科院分区：
文献类型：
--
作者：
Gailly, P.;Jouret, F.;Devuyst, O.
近端小管（PT）功能障碍与不同程度的溶质浪费和低分子蛋白尿有关。我们使用clc -5缺陷（Clcn5Y/-）小鼠的PT细胞（一种完善的登特病模型）测量了遗传性PT疾病模型中的代谢后果和适应机制。与来自对照小鼠的细胞相比，来自突变小鼠的细胞增殖标志物（Ki67、增殖细胞核抗原（PCNA）和细胞周期蛋白E）和氧化清除剂（超氧化物歧化酶I和硫氧还蛋白）的表达增加。转录组和蛋白质分析显示，在分散的PT细胞中，敲除小鼠以肾脏特异性方式四倍诱导III型碳酸酐酶。肾特异性碳酸酐酶III型（CAIII）上调在其他缺乏多配体受体巨galin的小鼠和因CLCN5失活突变而患有邓特病的患者中得到证实。III型酶在缺乏CIC-5或meggalin的小鼠、邓特病患者的尿液和暴露于氧化应激的PT细胞系中特异性检测到。我们的研究表明，小鼠和男性缺乏PT CIC-5与CAIII诱导、细胞增殖增加和氧化应激有关。
Dysfunction of the proximal tubule (PT) is associated with variable degrees of solute wasting and low-molecular-weight proteinuria. We measured metabolic consequences and adaptation mechanisms in a model of inherited PT disorders using PT cells of ClC-5-deficient (Clcn5Y/-) mice, a well-established model of Dent's disease. Compared to cells taken from control mice, those from the mutant mice had increased expression of markers of proliferation (Ki67, proliferative cell nuclear antigen (PCNA), and cyclin E) and oxidative scavengers (superoxide dismutase I and thioredoxin). Transcriptome and protein analyses showed fourfold induction of type III carbonic anhydrase in a kidney-specific manner in the knockout mice located in scattered PT cells. Kidney-specific carbonic anhydrase type III (CAIII) upregulation was confirmed in other mice lacking the multiligand receptor megalin and in a patient with Dent's disease due to an inactivating CLCN5 mutation. The type III enzyme was specifically detected in the urine of mice lacking CIC-5 or megalin, patients with Dent's disease, and in PT cell lines exposed to oxidative stress. Our study shows that lack of PT CIC-5 in mice and men is associated with CAIII induction, increased cell proliferation, and oxidative stress.