Heat Shock Protein 72 Antagonizes STAT3 Signaling to Inhibit Fibroblast Accumulation in Renal Fibrogenesis.
Heat Shock Protein 72 Antagonizes STAT3 Signaling to Inhibit Fibroblast Accumulation in Renal Fibrogenesis.
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DOI：
10.1016/j.ajpath.2015.11.016
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Yi Zhou;Shirong Cao;Huiyan Li;X. Peng;Yating Wang;Jin-jin Fan;Yihan H Wang;S. Zhuang;
中科院分区：
文献类型：
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作者：
Yi Zhou;Shirong Cao;Huiyan Li;X. Peng;Yating Wang;Jin-jin Fan;Yihan H Wang;S. Zhuang;
热休克蛋白72（HSP 72）已被证明可以减轻单侧输尿管梗阻诱导的肾纤维化。HSP 72在肾纤维化发展过程中是否对成纤维细胞增殖有直接影响尚不清楚。在此，我们首次证实了增加的HSP 72表达发生在纤维化的人肾脏。使用三种不同的肾纤维化动物模型，内源性HSP 72表达的药理学下调或基因缺失加剧了STAT 3磷酸化、成纤维细胞增殖和肾小管间质纤维化。相比之下，用HSP 72的特异性诱导剂香叶基香叶基丙酮处理，可以减少磷酸化STAT 3并保护动物免受肾脏纤维化。在培养的肾间质成纤维细胞中，HSP 72的过表达可以阻止转化生长因子（TGF）-β1诱导的细胞活化和增殖，这一点通过抑制α-平滑肌肌动蛋白、纤连蛋白和胶原蛋白I/III的表达以及减少细胞数量来证明。和DNA合成。力学研究表明，过表达HSP 72减弱TGF-β诱导的STAT 3磷酸化和核转位及其下游蛋白表达。然而，HSP 72的siRNA敲低增加了TGF-β诱导的STAT 3活性和成纤维细胞增殖。异位表达的组成型活性STAT 3赋予抵抗热休克蛋白72抑制成纤维细胞增殖。因此，HSP 72通过靶向STAT 3通路阻断肾纤维化中的成纤维细胞活化和增殖，并可作为慢性肾脏疾病的新型治疗剂，而不管病因如何。
Heat shock protein 72 (HSP72) has been shown to attenuate unilateral ureteral obstruction–induced kidney fibrosis. It remains unknown whether HSP72 has direct effects on fibroblast proliferation in the renal fibrotic evolution. Herein, we first confirmed that increased HSP72 expression occurred in fibrotic human kidneys. Using three different animal models of kidney fibrosis, pharmacological down-regulation or genetic deletion of endogenous HSP72 expression exacerbated STAT3 phosphorylation, fibroblast proliferation, and tubulointerstitial fibrosis. In contrast, treatment with geranylgeranyl acetone, a specific inducer of HSP72, reduced phosphorylated STAT3 and protected animals from kidney fibrosis. In cultured renal interstitial fibroblasts, overexpression of HSP72 blocked transforming growth factor (TGF)-β1–induced cell activation and proliferation, as evidenced by inhibiting expression of α-smooth muscle actin, fibronectin, and collagen I/III, as well as by reducing cell numbers and DNA synthesis. Mechanical studies showed that overexpressed HSP72 attenuated TGF-β–induced phosphorylation and nuclear translocation of STAT3 and its downstream protein expression. However, siRNA knockdown of HSP72 increased TGF-β–induced STAT3 activity and fibroblast proliferation. Ectopic expression of a constitutively active STAT3 conferred resistance to HSP72 inhibition of fibroblast proliferation. Thus, HSP72 blocks fibroblast activation and proliferation in renal fibrosis via targeting the STAT3 pathway and may serve as a novel therapeutic agent for chronic kidney disease regardless of the etiology.