Tubulointerstitial fibrosis is characterized by accumulation of the extracellular matrix in the interstitium. Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, is known for promoting cancer metastasis, invasion, and stromal fibrosis in various organs. Our previous study demonstrated expression of LOXL2 in kidney podocytes and tubular epithelial cells, and the association between elevated LOXL2 and tubulointerstitial fibrosis. The present study evaluated the effect of LOXL2 inhibition using an inhibitory monoclonal antibody (AB0023) on tubulointerstitial fibrosis in a folic acid-induced tubulointerstitial fibrosis mouse model. We also evaluated the association of LOXL2 with epithelial-mesenchymal transformation related molecules in vitro using HK-2 cells. Our data demonstrate that AB0023 prevented the progression of tubulointerstitial fibrosis significantly, as determined by trichrome and picro-sirius red staining, as well as the total collagen assay. The mean expression of phosphorylated Smad2 and Smad4 was lower in the AB0023-treated group although it was not statistically significant. Following transforming growth factor-β (TGF-β) challenge, LOXL2-deficient HK-2 cells exhibited significantly lower expression of the mesenchymal markers vimentin and fibronectin than control HK-2 cells. In conclusion, LOXL2 inhibition ameliorates renal fibrosis through the TGF-β/Smad signalling pathway.

中文翻译：

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抑制赖氨酰氧化酶样2改善叶酸诱导的肾小管间质纤维化

肾小管间质纤维化的特征是间质中细胞外基质的积累。类赖氨酰氧化酶家族成员之一的类赖氨酰氧化酶2（LOXL2）以促进各种器官中的癌症转移，侵袭和间质纤维化而闻名。我们先前的研究证明了LOXL2在肾脏足细胞和肾小管上皮细胞中的表达，以及LOXL2升高与肾小管间质纤维化之间的关系。本研究评估了叶酸诱导的肾小管间质纤维化小鼠模型中使用抑制性单克隆抗体（AB0023）对LOXL2的抑制作用对肾小管间质纤维化的影响。我们还使用HK-2细胞在体外评估了LOXL2与上皮-间质转化相关分子的关联。我们的数据表明，通过三色和皮西里乌斯红染色以及总胶原蛋白测定，AB0023显着阻止了肾小管间质纤维化的发展。磷酸化的Smad2和Smad4的平均表达在AB0023治疗组中较低，尽管无统计学意义。转化生长因子-β（TGF-β）攻击后，LOXL2缺陷型HK-2细胞的间充质标记波形蛋白和纤连蛋白的表达明显低于对照HK-2细胞。总之，LOXL2抑制可通过TGF-β/ Smad信号通路改善肾纤维化。磷酸化的Smad2和Smad4的平均表达在AB0023治疗组中较低，尽管无统计学意义。转化生长因子-β（TGF-β）攻击后，LOXL2缺陷型HK-2细胞的间充质标记波形蛋白和纤连蛋白的表达明显低于对照HK-2细胞。总之，LOXL2抑制可通过TGF-β/ Smad信号通路改善肾纤维化。磷酸化的Smad2和Smad4的平均表达在AB0023治疗组中较低，尽管无统计学意义。转化生长因子-β（TGF-β）攻击后，LOXL2缺陷型HK-2细胞的间充质标记波形蛋白和纤连蛋白的表达明显低于对照HK-2细胞。总之，LOXL2抑制可通过TGF-β/ Smad信号通路改善肾纤维化。