HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury
HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury
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DOI：
10.1152/ajprenal.00484.2014
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发表时间：
2015-01-01
影响因子：
4.2
通讯作者：
Chen, Shi-You
中科院分区：
文献类型：
--
作者：
Tian, Shaojiang;Zhang, Lansing;Chen, Shi-You
先前的研究表明巨噬细胞表型多样性参与肾纤维化的进展。然而，促进 M1 或 M2 表型的因素以及这些极化巨噬细胞在肾损伤和纤维化中的功能仍然很大程度上未知。在本研究中，我们发现在单侧输尿管梗阻（UUO）早期，肾间质中聚集的巨噬细胞主要表现为M1表型。从肾小管上皮细胞和间质巨噬细胞表达和释放的高迁移率族盒 1 (HMGB1) 蛋白对于 M1 巨噬细胞转变至关重要。 HMGB1 显着诱导巨噬细胞中 M1 标记物诱导型一氧化氮合酶的表达，同时降低 M2 标记物 IL-10。此外，甘草酸衍生物（HMGB1 释放阻断剂）可减少 UUO 介导的肾损伤并改善 UUO 诱导的肾纤维化。有趣且重要的是，UUO导致梗阻输尿管中积聚的尿液pH值降低，而酸化尿液在体外诱导肾小管上皮细胞和巨噬细胞释放HMGB1。我们的数据表明，HMGB1 是 UUO 早期促进 M1 极化的重要贡献者。抑制 HMGB1 释放可能会改变巨噬细胞表型，有助于保护肾组织免受损伤和纤维化。
Previous studies have indicated that macrophage phenotype diversity is involved in the progression of renal fibrosis. However, the factors facilitating M1 or M2 phenotypes and the function of these polarized macrophages in kidney injury and fibrosis remain largely unknown. In the present study, we found that macrophages accumulated in the kidney interstitium exhibited mainly as the M1 phenotype at the early stage of unilateral ureter obstruction (UUO). High-mobility group box 1 (HMGB1) protein expressed and released from tubular epithelial cells and interstitial macrophages was essential for the M1 macrophage transition. HMGB1 significantly induced the expression of the M1 marker inducible nitric oxide synthase while decreasing the M2 marker IL-10 in macrophages. Moreover, a glycyrrhizic acid derivative, a blocker of HMGB1 release, reduced UUO-mediated kidney injury and ameliorated UUO-induced renal fibrosis. Interestingly and importantly, UUO caused a low pH value in the urine accumulated in the obstructed ureter, and the acidified urine induced HMGB1 release from tubular epithelial cells and macrophages in vitro. Our data demonstrate that HMGB1 is an essential contributor in facilitating M1 polarization at the early stage of UUO. Inhibition of HMGB1 release may alter macrophage phenotype and contribute to the protection of kidney tissue from injury and fibrosis.