Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice
Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice
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DOI：
10.1038/s41419-019-2085-0
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发表时间：
2019-11
影响因子：
9
通讯作者：
Chao Zheng;Lan Huang;Wu Luo;Weihui Yu;Xueting Hu;X. Guan;Yan Cai;C. Zou;Haimin Yin;
中科院分区：
文献类型：
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作者：
Chao Zheng;Lan Huang;Wu Luo;Weihui Yu;Xueting Hu;X. Guan;Yan Cai;C. Zou;Haimin Yin;
近年来的研究表明，信号转导和转录激活因子3（STAT 3）是糖尿病肾病（DN）发生发展的重要信号通路之一。在这里，我们研究了药物阻断STAT 3限制DN进展的假设。用选择性STAT 3抑制剂S3 I-201治疗16周显著减轻链脲佐菌素（STZ）诱导的糖尿病小鼠的肾损伤，与糖尿病小鼠肾脏中TGF-β1、ACE/AT 1和VEGF的表达下调相关。通过在糖尿病小鼠中注射表达STAT 3 shRNA的AAV 2，使用小鼠肾脏中的STAT 3基因敲低证实了类似的结果。免疫荧光双染法检测STAT 3在肾组织中的定位，结果表明STAT 3主要表达于肾小管上皮细胞。正如预期的那样，在肾小管上皮NRK-52 E细胞中，高糖（HG）诱导的TGF-β1、ACE/AT 1和VEGF的过表达被S3 I-201预处理以及使用特异性siRNA序列基因敲低STAT 3所消除。这项研究发现，肾小管上皮细胞有助于STAT 3介导的DN进展，并提供了第一个证据表明，STAT 3的药理学抑制减轻DN。
Recent evidences indicate that signal transducer and activator of transcription 3 (STAT3) is one of the crucial signaling pathways in the progression of diabetic nephropathy (DN). Here, we investigated the hypothesis that pharmacological blockade of STAT3 limits the progression of DN. Treatment with selective STAT3 inhibitor, S3I-201 for 16 weeks significantly attenuated kidney injuries in streptozotocin (STZ) induced diabetic mice, associated with downregulated expression of TGF-β1, ACE/AT1, and VEGF in diabetic mouse kidneys. Similar results were confirmed using genetic knockdown of STAT3 in mouse kidneys by injections of AAV2 expressing STAT3 shRNA in diabetic mouse. Further, STAT3 localization in kidney tissue was evaluated using immunofluorescent double-staining analysis, which indicated that STAT3 expression was mainly in the tubular epithelial cells. As expected, in renal tubular epithelial NRK-52E cells, high glucose (HG)-induced overexpression of TGF-β1, ACE/AT1, and VEGF were abrogated by S3I-201 pretreatment, as well as by genetic knockdown of STAT3 using specific siRNA sequence. This study found that renal tubular epithelial cells contributed to STAT3-mediated progression of DN and provided the first evidence that pharmacological inhibition of STAT3 attenuates DN.