Twist-related protein 1 induces epithelial-mesenchymal transition and renal fibrosis through the upregulation of complement 3.
Twist-related protein 1 induces epithelial-mesenchymal transition and renal fibrosis through the upregulation of complement 3.
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DOI：
10.1371/journal.pone.0272917
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Abe, Masanori
中科院分区：
文献类型：
--
作者：
Otsuki, Tomoyasu;Fukuda, Noboru;Chen, Lan;Tsunemi, Akiko;Abe, Masanori
我们已经证明，补体3（C3）上调，并诱导上皮间质转化（EMT）现象和肾纤维化在单侧输尿管梗阻（UUO）的肾脏。我们研究了扭转相关蛋白1（TWIST 1）在EMT现象和肾纤维化中的作用，通过在小鼠UUO模型中使用靶向TWIST 1的基因沉默剂吡咯-咪唑（PI）聚酰胺上调C3。我们设计并合成了靶向小鼠pre-pro C3启动子上TWIST 1结合位点的PI聚酰胺。PI聚酰胺可显著抑制γ-干扰素诱导的肾小管上皮细胞C3 mRNA表达的增加。免疫荧光显示UUO肾组织中E-cadherin表达减少，α-平滑肌肌动蛋白（α-SMA）表达增强，表现为EMT现象。TWIST 1和C3的表达在UUO肾中比对侧通畅肾（CUK）中显著增加。转化生长因子-β1（TGF-β1）、α-SMA和肾素mRNAs在UUO肾组织中的表达较CUK肾组织明显增加。与CUK相比，TWIST 1 PI聚酰胺的全身给药显著抑制了UUO肾脏中C3表达的增加。PI聚酰胺给药还抑制了UUO肾中TGF-β1、α-SMA和肾素mRNA的表达增加，并在组织学上改善了肾纤维化。这些结果表明TWIST 1通过TGF-β1上调C3表达诱导UUO小鼠模型的EMT现象和肾纤维化，TWIST 1 PI聚酰胺可能是一种治疗肾纤维化的新药。
We have demonstrated that complement 3 (C3) is upregulated and induces epithelial-mesenchymal transition (EMT) phenomenon and renal fibrosis in unilateral ureteral obstruction (UUO) kidney. We investigated roles of twist-related protein 1 (TWIST1) in EMT phenomenon and renal fibrosis through C3 upregulation in a mouse UUO model with gene silencer pyrrole-imidazole (PI) polyamides targeting TWIST1. We designed and synthesized PI polyamides targeting TWIST1 binding site on mouse pre-pro C3 promoter. Increased expression C3 mRNA with interferon-γ was significantly inhibited with PI polyamide in nephrotubular epithelial cells. Immunofluorescence showed suppression of E-cadherin and enhancement of α-smooth muscle actin (α-SMA) stainings as EMT phenomena in UUO kidney. TWIST1 and C3 expression was significantly increased in UUO kidney versus contralateral unobstructed kidney (CUK). Expression of transforming growth factor-β1 (TGF-β1), α-SMA and renin mRNAs was increased in UUO kidney versus CUK. Systemic administration of TWIST1 PI polyamide significantly suppressed increased C3 expression in UUO kidney versus CUK. PI polyamide administration also suppressed the increased expression of TGF-β1, α-SMA and renin mRNAs and histologically improved renal fibrosis in UUO kidney. These findings indicate that TWIST1 induces EMT phenomenon and renal fibrosis by TGF-β1 upregulation of C3 in mouse UUO model and that TWIST1 PI polyamide may be a novel medicine for renal fibrosis.
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影响因子：
4.6
作者：
Otsuki, Masari;Fukuda, Noboru;Abe, Masanori
通讯作者：
Abe, Masanori
DOI：
10.4049/jimmunol.1501886
发表时间：
2016-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cho MS;Rupaimoole R;Choi HJ;Noh K;Chen J;Hu Q;Sood AK;Afshar-Kharghan V
通讯作者：
Afshar-Kharghan V
影响因子：
82.9
作者：
Zeisberg, M;Hanai, J;Kalluri, R
通讯作者：
Kalluri, R
影响因子：
64.8
作者：
Trauger, JW;Baird, EE;Dervan, PB
通讯作者：
Dervan, PB
影响因子：
13.6
作者：
Fukuda, Noboru;Ueno, Takahiro;Serie, Kazuo
通讯作者：
Serie, Kazuo