Overexpression of Heme Oxygenase-1 Prevents Renal Interstitial Inflammation and Fibrosis Induced by Unilateral Ureter Obstruction.
Overexpression of Heme Oxygenase-1 Prevents Renal Interstitial Inflammation and Fibrosis Induced by Unilateral Ureter Obstruction.
复制标题
血红素加氧酶-1 的过度表达可预防单侧输尿管梗阻引起的肾间质炎症和纤维化
DOI：
10.1371/journal.pone.0147084
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Chen X;Wei SY;Li JS;Zhang QF;Wang YX;Zhao SL;Yu J;Wang C;Qin Y;Wei QJ;Lv GX;Li B
肾纤维化在慢性肾脏疾病的发生和发展中起着重要作用。血红素加氧酶-1（heme oxygenase-1，HO-1）作为一种细胞保护分子参与多种生物学过程，包括抗炎、抗氧化、抗凋亡、抗增殖和免疫调节等作用。然而，HO-1预防肾间质纤维化的机制仍不清楚。本研究采用HO-1转基因（TG）小鼠建立单侧输尿管梗阻（UUO）模型，观察HO-1对肾纤维化的影响，并探讨其可能的作用机制。我们发现HO-1在UUO后TG和野生型（WT）小鼠的肾脏中适应性上调。TG小鼠HO-1 mRNA和蛋白表达水平均高于WT小鼠。HO-1表达在UUO后进一步增强，并在整个实验过程中保持高水平。TG组肾间质纤维化程度较WT组明显减轻。此外，HO-1的过表达抑制肾小管周围毛细血管的损失。此外，HO-1过表达可抑制UUO诱导的肌成纤维细胞活化和增殖。HO-1抑制UUO小鼠肾小管间质巨噬细胞浸润，调节炎症细胞因子的分泌。我们还发现HO-1的高表达抑制了Wnt/β-catenin信号通路的重新激活，这可能在减轻肾纤维化中起关键作用。总之，这些数据表明HO-1可能通过调节炎症反应和Wnt/β-catenin信号传导来预防肾小管间质纤维化。这项研究提供的证据表明，HO-1水平的增加可能是一种治疗策略，对肾间质纤维化。
Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases. Many studies have demonstrated that heme oxygenase-1 (HO-1) is involved in diverse biological processes as a cytoprotective molecule, including anti-inflammatory, anti-oxidant, anti-apoptotic, antiproliferative, and immunomodulatory effects. However, the mechanisms of HO-1 prevention in renal interstitial fibrosis remain unknown. In this study, HO-1 transgenic (TG) mice were employed to investigate the effect of HO-1 on renal fibrosis using a unilateral ureter obstruction (UUO) model and to explore the potential mechanisms. We found that HO-1 was adaptively upregulated in kidneys of both TG and wild type (WT) mice after UUO. The levels of HO-1 mRNA and protein were increased in TG mice compared with WT mice under normal conditions. HO-1 expression was further enhanced after UUO and remained high during the entire experimental process. Renal interstitial fibrosis in the TG group was significantly attenuated compared with that in the WT group after UUO. Moreover, overexpression of HO-1 inhibited the loss of peritubular capillaries. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by HO-1 overexpression. Furthermore, HO-1 restrained tubulointerstitial infiltration of macrophages and regulated the secretion of inflammatory cytokines in UUO mice. We also found that high expression of HO-1 inhibited reactivation of Wnt/β-catenin signaling, which could play a crucial role in attenuating renal fibrosis. In conclusion, these data suggest that HO-1 prevents renal tubulointerstitial fibrosis possibly by regulating the inflammatory response and Wnt/β-catenin signaling. This study provides evidence that augmentation of HO-1 levels may be a therapeutic strategy against renal interstitial fibrosis.