Absence of chloride intracellular channel 4 (CLIC4) predisposes to acute kidney injury but has minimal impact on recovery.
Absence of chloride intracellular channel 4 (CLIC4) predisposes to acute kidney injury but has minimal impact on recovery.
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DOI：
10.1186/1471-2369-15-54
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发表时间：
2014-04-03
期刊：
影响因子：
2.3
通讯作者：
Cheng YW
中科院分区：
文献类型：
--
作者：
Edwards JC;Bruno J;Key P;Cheng YW
CLIC 4是CLIC蛋白家族的成员，最近被证明在分化的角质形成细胞中易位到细胞核，在那里它增强TGFβ驱动的基因调控。由于已知TGFβ信号传导在对急性肾损伤的纤维化反应中起重要作用，并且由于CLIC 4在肾脏中大量表达，因此我们假设CLIC 4可能在对急性肾损伤的反应中起作用。分析先前描述的Clic 4缺失小鼠的不存在CLIC 4对生长、发育和对肾损伤的反应的影响。测定匹配的WT和Clic 4缺失小鼠的肾脏大小、肾小球计数和肾小管周围毛细血管密度。使WT和Clic 4缺失小鼠的群组经受急性肾损伤的叶酸模型。通过血浆尿素氮（BUN）评估急性损伤和长期功能恢复的程度;通过肾切片的组织化学评估和残余肾质量确定长期纤维化/瘢痕形成。通过磷酸化SMAD 2和3的半定量蛋白质印迹评估TGFβ信号传导途径的活化。CLIC 4在肾近端小管细胞的顶端以及肾小球和管周毛细血管的内皮细胞中大量表达。CLIC 4缺失小鼠体积小，肾脏较小，肾小球较少，肾小管周围毛细血管网密度较低，蛋白尿增加。Clic 4缺失小鼠显示对叶酸诱导的急性肾损伤的易感性增加，但在从急性损伤恢复方面没有差异，在损伤后没有CLIC 4的核重新分布，并且在TGFβ信号传导途径的活化方面没有显著差异，如SMAD 2和3的磷酸化水平所反映的。CLIC 4的缺失导致与其在血管生成中的已知作用一致的形态学变化。这些变化可能至少部分导致急性肾损伤易感性增加。然而，CLIC 4的缺乏对急性损伤后的功能恢复或纤维化的程度没有显著影响，表明CLIC 4在参与响应急性肾损伤的TGFβ信号传导中不起主要的非冗余作用。
CLIC4, a member of the CLIC family of proteins, was recently demonstrated to translocate to the nucleus in differentiating keratinocytes where it potentiates TGFβ-driven gene regulation. Since TGFβ signaling is known to play important roles in the fibrotic response to acute kidney injury, and since CLIC4 is abundantly expressed in kidney, we hypothesized that CLIC4 may play a role in the response to acute kidney injury. Previously described Clic4 null mice were analyzed for the effect of absence of CLIC4 on growth, development and response to kidney injury. Kidney size, glomerular counts and density of peritubular capillaries of matched WT and Clic4 null mice were determined. Cohorts of WT and Clic4 null mice were subjected to the folic acid model of acute kidney injury. Extent of acute injury and long term functional recovery were assessed by plasma blood urea nitrogen (BUN); long term fibrosis/scarring was determined by histochemical assessment of kidney sections and by residual renal mass. Activation of the TGFβ signaling pathway was assessed by semi-quantitative western blots of phosphorylated SMADs 2 and 3. CLIC4 is abundantly expressed in the apical pole of renal proximal tubule cells, and in endothelial cells of glomerular and peritubular capillaries. CLIC4 null mice are small, have smaller kidneys with fewer glomeruli and less dense peritubular capillary networks, and have increased proteinuria. The Clic4 null mice show increased susceptibility to folic acid-induced acute kidney injury but no difference in recovery from acute injury, no nuclear redistribution of CLIC4 following injury, and no significant difference in activation of the TGFβ-signaling pathway as reflected in the level of phosphorylation of SMADs 2 and 3. Absence of CLIC4 results in morphologic changes consistent with its known role in angiogenesis. These changes may be at least partially responsible for the increased susceptibility to acute kidney injury. However, the absence of CLIC4 has no significant impact on the extent of functional recovery or fibrosis following acute injury, indicating that CLIC4 does not play a major non-redundant role in the TGFβ signaling involved in response to acute kidney injury.