Tubule-derived INHBB promotes interstitial fibroblast activation and renal fibrosis
Tubule-derived INHBB promotes interstitial fibroblast activation and renal fibrosis
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肾小管来源的 INHBB 促进间质成纤维细胞活化和肾纤维化
DOI：
10.1002/path.5798
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发表时间：
2021-10-20
影响因子：
7.3
通讯作者：
Zang, Yuhui
中科院分区：
文献类型：
--
作者：
Sun, Yanyan;Cai, Huimin;Zang, Yuhui
肌成纤维细胞激活的上游刺激对于理解肾纤维化的机制具有重要意义。激活素B是tgf - β家族的一员，作为抑制素亚单位β B （INHBB）的同二聚体存在，但其在肾纤维化中的作用尚不清楚。我们发现INHBB在各种肾纤维化模型和人慢性肾病肾纤维化标本中表达显著升高。值得注意的是，INHBB的增加主要发生在小管上皮细胞（TECs）。在体内，抑制INHBB阻断了间质成纤维细胞的激活，改善了单侧输尿管梗阻或缺血再灌注损伤引起的肾纤维化，而在tec中异位表达INHBB能够激活间质成纤维细胞并引发间质纤维化。在体外，在tec中过表达INHBB导致激活素B的分泌，从而通过激活素B/Smad信号通路促进间质成纤维细胞的增殖和活化。此外，激活素B/Smad信号的抑制可减弱管状INHBB引起的纤维化反应。机制上，INHBB的上调依赖于受损tec中的转录因子Sox9。临床分析还发现人类标本中Sox9和INHBB表达呈正相关，表明Sox9/INHBB轴是肾纤维化的积极调节因子。总之，小管源性INHBB通过以旁分泌方式激活周围成纤维细胞参与肾纤维化的发病机制，因此显示出作为潜在的治疗靶点。(c) 2021大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
Upstream stimuli for myofibroblast activation are of considerable interest for understanding the mechanisms underlying renal fibrosis. Activin B, a member of the TGF-beta family, exists as a homodimer of inhibin subunit beta B (INHBB), but its role in renal fibrosis remains unknown. We found that INHBB expression was significantly increased in various renal fibrosis models and human chronic kidney disease specimens with renal fibrosis. Notably, the increase of INHBB occurred mainly in the tubular epithelial cells (TECs). In vivo, inhibiting INHBB blocked the activation of interstitial fibroblasts and ameliorated the renal fibrosis induced by unilateral ureteral obstruction or ischemia-reperfusion injury, while ectopic expression of INHBB in the TECs was able to activate interstitial fibroblasts and initiate interstitial fibrosis. In vitro, overexpression of INHBB in TECs led to the secretion of activin B, thereby promoting the proliferation and activation of interstitial fibroblasts through activin B/Smad signaling. Furthermore, inhibition of activin B/Smad signaling attenuated the fibrotic response caused by tubular INHBB. Mechanistically, the upregulation of INHBB depended on the transcription factor Sox9 in the injured TECs. Clinical analyses also identified a positive correlation between Sox9 and INHBB expression in human specimens, suggesting the Sox9/INHBB axis as a positive regulator of renal fibrosis. In conclusion, tubule-derived INHBB is implicated in the pathogenesis of renal fibrosis by activating the surrounding fibroblasts in a paracrine manner, thereby exhibiting as a potential therapeutic target. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.