Cilomilast Ameliorates Renal Tubulointerstitial Fibrosis by Inhibiting the TGF-β1-Smad2/3 Signaling Pathway.
Cilomilast Ameliorates Renal Tubulointerstitial Fibrosis by Inhibiting the TGF-β1-Smad2/3 Signaling Pathway.
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Cilomilast通过抑制TGF-β1-SMAD2/3信号传导途径来改善肾小管间隙纤维化。
DOI：
10.3389/fmed.2020.626140
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发表时间：
2020
影响因子：
3.9
通讯作者：
Jia Z
中科院分区：
文献类型：
--
作者：
Xu M;Li S;Wang J;Huang S;Zhang A;Zhang Y;Gu W;Yu X;Jia Z
背景资料：肾小管间质纤维化是慢性肾脏病（CKD）的主要病理特征，目前临床上尚无满意的治疗方法。西洛司特是第二代选择性磷酸二酯酶-4抑制剂，但其在CKD肾小管间质纤维化中的作用尚不清楚。材料和方法：将西洛司特应用于单侧输尿管梗阻（UUO）小鼠和TGF-β1刺激的肾成纤维细胞（NRK-49 F）。采用组织学、Western blotting、real-time PCR和免疫组织化学方法检测UUO或TGF-β1刺激后肾小管间质纤维化和炎症反应。检测KIM-1和NGAL的表达，评价UUO小鼠肾小管损伤。结果如下：在体内，免疫组化和蛋白质印迹数据表明，西洛司特治疗抑制细胞外基质沉积，促纤维化基因表达，和炎症反应。此外，西洛司特预防UUO小鼠中的肾小管损伤，如通过肾脏中KIM-1和NGAL的表达减少所证明的。在体外，西洛司特减弱了TGF-β1刺激的成纤维细胞活化，如纤连蛋白、α-SMA、胶原I和胶原III表达减少所示。西洛司特还抑制TGF-β1处理的成纤维细胞中TGF-β1-Smad 2/3信号转导的激活。结论：本研究的结果表明，西洛司特可能通过抑制TGF-β1-Smad 2/3信号传导，对CKD中的肾小管间质纤维化具有保护作用，表明该药物在治疗CKD中的转化潜力。
Background: Renal tubulointerstitial fibrosis is the key pathological feature in chronic kidney diseases (CKDs) with no satisfactory therapies in clinic. Cilomilast is a second-generation, selective phosphodiesterase-4 inhibitor, but its role in renal tubulointerstitial fibrosis in CKD remains unclear. Material and Methods: Cilomilast was applied to the mice with unilateral ureteric obstruction (UUO) and renal fibroblast cells (NRK-49F) stimulated by TGF-β1. Renal tubulointerstitial fibrosis and inflammation after UUO or TGF-β1 stimulation were examined by histology, Western blotting, real-time PCR and immunohistochemistry. KIM-1 and NGAL were detected to evaluate tubular injury in UUO mice. Results: In vivo, immunohistochemistry and western blot data demonstrated that cilomilast treatment inhibited extracellular matrix deposition, profibrotic gene expression, and the inflammatory response. Furthermore, cilomilast prevented tubular injury in UUO mice, as manifested by reduced expression of KIM-1 and NGAL in the kidney. In vitro, cilomilast attenuated the activation of fibroblast cells stimulated by TGF-β1, as shown by the reduced expression of fibronectin, α-SMA, collagen I, and collagen III. Cilomilast also inhibited the activation of TGF-β1-Smad2/3 signaling in TGF-β1-treated fibroblast cells. Conclusion: The findings of this study suggest that cilomilast is protective against renal tubulointerstitial fibrosis in CKD, possibly through the inhibition of TGF-β1-Smad2/3 signaling, indicating the translational potential of this drug in treating CKD.
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影响因子：
4.6
作者：
Popper, Bastian;Rammer, Marian Theodor;Lange-Sperandio, Barbel
通讯作者：
Lange-Sperandio, Barbel
用白术内酯 I 抑制增殖相关信号级联反应可减少肌成纤维细胞表型和肾纤维化
影响因子：
5.8
作者：
Guo, Yangyang;Xiao, Yanyi;Bai, Yongheng
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Bai, Yongheng
DOI：
10.1152/ajprenal.00402.2018
发表时间：
2018-12-01
影响因子：
4.2
作者：
Ma, Zhengwei;Wei, Qingqing;Bong, Zheng
通讯作者：
Bong, Zheng
影响因子：
9.2
作者：
Lan HY
通讯作者：
Lan HY
影响因子：
27.4
作者：
Maier, Christiane;Ramming, Andreas;Beyer, Christian
通讯作者：
Beyer, Christian