Transcription Factor Trps1 Promotes Tubular Cell Proliferation after Ischemia-Reperfusion Injury through cAMP-Specific 3′,5′-Cyclic Phosphodiesterase 4D and AKT
Transcription Factor Trps1 Promotes Tubular Cell Proliferation after Ischemia-Reperfusion Injury through cAMP-Specific 3′,5′-Cyclic Phosphodiesterase 4D and AKT
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转录因子 Trps1 通过 cAMP 特异性 3',5'-环磷酸二酯酶 4D 和 AKT 促进缺血再灌注损伤后肾小管细胞增殖
DOI：
10.1681/asn.2016010009
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发表时间：
2017-02-01
影响因子：
13.6
通讯作者：
He Ya-Ni
中科院分区：
文献类型：
--
作者：
Yang Ju-Rong;Chen Ke-Hong;He Ya-Ni
Trps 1是肾脏发育过程中上皮细胞形态发生所必需的转录因子，但Trps 1在缺血再灌注（I/R）诱导的阿基中的作用尚不清楚。我们的研究探讨Trps 1在大鼠急性I/R后肾脏修复过程中的表达，并探讨Trps 1促进肾小管上皮细胞增殖的分子机制。Trps 1表达与I/R损伤后肾修复程度呈正相关。与野生型大鼠相比，敲低Trps 1的大鼠在中度I/R模型中表现出明显延迟的肾修复，GFR水平较低，形态学损伤更严重，而过表达Trps 1的大鼠在严重I/R损伤后表现出明显加速的肾修复。此外，敲低Trps 1抑制和过表达Trps 1促进大鼠肾小管上皮细胞的增殖。染色质免疫沉淀测序和RT-PCR结果显示Trps 1调控cAMP特异性3 '，5'-环磷酸二酯酶4D（Pde 4d）的表达。敲低Trps 1可降低大鼠肾脏Pde 4d和磷酸化Akt的蛋白表达，双荧光素酶分析显示Trps 1可直接激活Pde 4d的转录。此外，敲低Pde 4d或用磷脂酰肌醇3激酶抑制剂wortmannin处理显著抑制Trps 1诱导的体外肾小管细胞增殖。Trps 1可能通过Pde 4d/磷脂酰肌醇3激酶/AKT信号通路促进肾小管细胞增殖，提示Trps 1是I/R损伤后肾脏修复的潜在治疗靶点。
Trichorhinophalangeal 1 (Trps1) is a transcription factor essential for epithelial cell morphogenesis during kidney development, but the role of Trps1 in AKI induced by ischemia-reperfusion (I/R) remains unclear. Our study investigated Trps1 expression during kidney repair after acute I/R in rats and explored the molecular mechanisms by which Trps1 promotes renal tubular epithelial cell proliferation. Trps1 expression positively associated with the extent of renal repair after I/R injury. Compared with wild-type rats, rats with knockdown of Trps1 exhibited significantly delayed renal repair in the moderate I/R model, with lower GFR levels and more severe morphologic injury, whereas rats overexpressing Trps1 exhibited significantly accelerated renal repair after severe I/R injury. Additionally, knockdown of Trps1 inhibited and overexpression of Trps1 enhanced the proliferation of renal tubular epithelial cells in rats. Chromatin immuno-precipitation sequencing assays and RT-PCR revealed that Trps1 regulated cAMP specific 3',5'-cyclic phosphodiesterase 4D (Pde4d) expression. Knockdown of Trps1 decreased the renal protein expression of Pde4d and phosphorylated Akt in rats, and dual luciferase analysis showed that Trps1 directly activated Pde4d transcription. Furthermore, knockdown of Pde4d or treatment with the phosphatidylinositol 3 kinase inhibitor wortmannin significantly inhibited Trps1 induced tubular cell proliferation in vitro. Trps1 may promote tubular cell proliferation through the Pde4d/phosphatidylinositol 3 kinase/AKT signaling pathway, suggesting Trps1 as a potential therapeutic target for kidney repair after I/R injury.