JMJD1A/NR4A1 Signaling Regulates the Procession of Renal Tubular Epithelial Interstitial Fibrosis Induced by AGEs in HK-2.
JMJD1A/NR4A1 Signaling Regulates the Procession of Renal Tubular Epithelial Interstitial Fibrosis Induced by AGEs in HK-2.
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JMJD1A/NR4A1信号调节HK-2中AGEs诱导的肾小管上皮间质纤维化进程
DOI：
10.3389/fmed.2021.807694
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发表时间：
2021
影响因子：
3.9
通讯作者：
Wang M
中科院分区：
文献类型：
--
作者：
Wang S;Zuo A;Jiang W;Xie J;Lin H;Sun W;Zhao M;Xia J;Shao J;Zhao X;Liang D;Yang A;Sun J;Wang M
糖尿病肾病是糖尿病患者最严重的并发症之一。晚期糖基化终产物（AGEs）可诱导肾小管上皮细胞（HK-2）发生上皮-间质转化（EMT），导致肾小管间质纤维化。然而，潜在的表观遗传机制仍有待进一步研究。在这项工作中，我们研究了JMJD 1A在DKD进展中的功能作用。在AGEs诱导的HK-2细胞中通过基因表达分析、RNA测序（RNA-seq）和JMJD 1A慢病毒敲减和过表达颗粒转染进行分子机制研究。结果表明，AGEs可上调JMJD 1A的表达，并使相关纤维化因子的表达增加。同时，在单侧肾切除加链脲佐菌素（STZ）诱导的DKD动物模型中，免疫组化染色显示，与对照组相比，模型组JMJD 1A、FN、COL 1的表达均增加，Masson染色结果也显示模型组有典型的纤维化改变。这与我们的体外实验结果一致。为了确定JMJD 1A的下游通路，我们通过RNA-seq筛选出JMJD 1A下游转录因子。进一步分析表明，JMJD 1A过表达可通过降低HK-2细胞NR 4A 1的表达而加速AGEs诱导的肾纤维化进程。同时，NR 4A 1抑制剂可促进HK-2细胞中Vim、a-SMA等纤维化相关因子的表达，加重纤维化进程。综上所述，JMJD 1A/NR 4A 1信号通路可调节AGEs诱导的HK-2肾小管上皮间质纤维化的进程。
Diabetic kidney disease (DKD) is one of the most serious complications of diabetic patients. Advanced glycation end products (AGEs) induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (HK-2), resulting in renal tubulointerstitial fibrosis. However, the underlying epigenetic mechanisms remain to be further investigated. In this work, we investigated the functional role of JMJD1A involved in DKD progression. The molecular mechanism study was performed in AGEs-induced HK-2 cells by gene expression analysis, RNA sequencing (RNA-seq), and JMJD1A lentiviral knockdown and overexpression particle transfection. The results showed that AGEs could upregulate JMJD1A, and the expressions of related fibrotic factor were also increased. At the same time, in the DKD animal model induced by unilateral nephrectomy plus streptozotocin (STZ), IHC immunohistochemical staining showed that compared with the control group, the expressions of JMJD1A, FN, and COL1 in the model group were all increased, masson staining results also show that the model group has typical fibrotic changes. This is consistent with the results of our in vitro experiments. In order to determine the downstream pathway, we screened out JMJD1A downstream transcription factors by RNA-seq. Further analysis showed that JMJD1A overexpression could accelerate the progression of AGEs-induced renal fibrosis by reducing the expression of NR4A1 in HK-2 cells. Meanwhile, NR4A1 inhibitor can promote the expression of fibrosis-related factors such as VIM, a-SMA in HK-2 cells, and aggravate the process of fibrosis. Taken together, JMJD1A/NR4A1 signaling can regulate the procession of renal tubular epithelial interstitial fibrosis induced by AGEs in HK-2.
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影响因子：
5.9
作者：
Kuroki S;Nakai Y;Maeda R;Okashita N;Akiyoshi M;Yamaguchi Y;Kitano S;Miyachi H;Nakato R;Ichiyanagi K;Shirahige K;Kimura H;Shinkai Y;Tachibana M
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Tachibana M
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Jiang, Nan
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21.3
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Hochedlinger, Konrad
影响因子：
19.6
作者：
Krolewski AS;Skupien J;Rossing P;Warram JH
通讯作者：
Warram JH
影响因子：
81.5
作者：
McIntyre, H. David;Catalano, Patrick;Damm, Peter
通讯作者：
Damm, Peter