Background and aim

As a proinflammatory cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in the progression of renal fibrosis by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14). However, the effect of Fn14 inhibition on tubular epithelial cell-mediated tubulointerstitial fibrosis remains unclear. This study aimed to elucidate the role of TWEAK/Fn14 interaction in the development of experimental tubulointerstitial fibrosis as well as the protective effect of Fn14 knockdown on proximal tubular epithelial cells.

Methods

A murine model of unilateral ureteral obstruction was constructed in both wild-type and Fn14-deficient BALB/c mice, followed by observation of the tubulointerstitial pathologies.

Results

Fn14 deficiency ameliorated the pathological changes, including inflammatory cell infiltration and cell proliferation, accompanied by reduced production of profibrotic factors and extracellular matrix deposition. In vitro experiments showed that TWEAK dose-dependently enhanced the expression of collagen I, fibronectin, and α-smooth muscle actin in proximal tubular epithelial cells. Interestingly, TWEAK also upregulated the expression levels of Notch1/Jagged1. Fn14 knockdown and Notch1/Jagged1 inhibition also mitigated the effect of TWEAK on these cells.

Conclusions

In conclusion, TWEAK/Fn14 signals contributed to tubulointerstitial fibrosis by acting on proximal tubular epithelial cells. Fn14 inhibition might be a therapeutic strategy for protecting against renal interstitial fibrosis.

中文翻译：

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抑制成纤维细胞生长因子诱导型 14 可减轻实验性肾小管间质纤维化和近端肾小管上皮细胞的促纤维化因子表达

 背景和目的

作为一种促炎细胞因子，肿瘤坏死因子样弱凋亡诱导剂 (TWEAK) 通过与其受体成纤维细胞生长因子-诱导型 14 (Fn14) 结合参与肾纤维化的进展。然而，Fn14 抑制对肾小管上皮细胞介导的肾小管间质纤维化的影响仍不清楚。本研究旨在阐明TWEAK/Fn14相互作用在实验性肾小管间质纤维化发展中的作用以及Fn14敲低对近端肾小管上皮细胞的保护作用。

 方法

在野生型和Fn14缺陷型 BALB/c 小鼠中构建单侧输尿管梗阻的小鼠模型，然后观察肾小管间质病理学。

 结果

Fn14缺乏改善了病理变化，包括炎症细胞浸润和细胞增殖，同时促纤维化因子产生减少和细胞外基质沉积。体外实验表明，TWEAK 剂量依赖性地增强近端肾小管上皮细胞中 I 型胶原蛋白、纤连蛋白和 α-平滑肌肌动蛋白的表达。有趣的是，TWEAK 还上调了 Notch1/Jagged1 的表达水平。 Fn14敲低和 Notch1/Jagged1 抑制也减轻了 TWEAK 对这些细胞的影响。

 结论

总之，TWEAK/Fn14 信号通过作用于近端肾小管上皮细胞而导致肾小管间质纤维化。 Fn14抑制可能是预防肾间质纤维化的一种治疗策略。