H2S alleviates renal injury and fibrosis in response to unilateral ureteral obstruction by regulating macrophage infiltration via inhibition of NLRP3 signaling.
H2S alleviates renal injury and fibrosis in response to unilateral ureteral obstruction by regulating macrophage infiltration via inhibition of NLRP3 signaling.
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DOI：
10.1016/j.yexcr.2019.111779
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发表时间：
2019-12
影响因子：
3.7
通讯作者：
Yueyuan Zhou;Xiaoyan Zhu;Xuan Wang;Yi Peng;Jiankui Du;Hong-ling Yin;Hui Yang;Xin Ni;Weiru Zhang
中科院分区：
文献类型：
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作者：
Yueyuan Zhou;Xiaoyan Zhu;Xuan Wang;Yi Peng;Jiankui Du;Hong-ling Yin;Hui Yang;Xin Ni;Weiru Zhang
肾纤维化是慢性肾脏病（CKD）的重要病理特征。硫化氢（H2S）稳态失调与CKD的发病机制有关。在此，将C57/BL 6小鼠分配至假手术组和单侧输尿管梗阻（UUO）组，其用NaHS或NLRP 3炎性体抑制剂16673-34-0处理3-14天。UUO小鼠表现出H2S产生的下调和阻塞肾脏中巨噬细胞浸润的增加。H2S供体NaHS处理减轻肾损伤和纤维化，并抑制M1和M2巨噬细胞浸润。UUO后肾组织NLPR 3炎性小体被激活，磷酸化核因子κB（NF-κB）p65亚基、磷酸化信号转导和转录激活因子6（STAT 6）和白细胞介素（IL）4蛋白水平升高。NLRP 3抑制剂灭活NF-κB和IL-4/STAT 6信号传导，抑制M1和M2巨噬细胞浸润，减轻UUO小鼠的肾损伤和纤维化。NaHS处理还抑制了梗阻肾脏中NLRP 3、NF-κB和IL-4/STAT 6的活化。总之，H2S对UUO诱导的肾损伤和纤维化的治疗作用至少部分是通过抑制M1和M2巨噬细胞浸润实现的。H2S抑制NLRP 3活化，随后使NF-κB和IL-4/STAT 6信号转导失活，这可能有助于H2S的抗炎和抗纤维化作用。
Renal fibrosis is a key pathological feature in chronic kidney diseases (CKDs). Dysregulation of hydrogen sulfide (H2S) homeostasis is implicated in the pathogenesis of CKDs. Here, C57/BL6 mice were allocated to Sham and unilateral ureteral obstruction (UUO) groups, which were treated with NaHS or NLRP3 inflammasome inhibitor 16673-34-0 for 3–14 days. UUO mice displayed downregulation of H2S production and increased macrophage infiltration in obstructed kidneys. H2S donor NaHS treatment attenuated renal damage and fibrosis and inhibited M1 and M2 macrophage infiltration. NLPR3 inflammasome was activated and levels of phosphorylated nuclear factor κB (NF-κB) p65 subunit, phosphorylated signal transducer and activator of transcription 6 (STAT6) and interleukin (IL)-4 protein were increased in the kidneys after UUO. NLRP3 inhibitor inactivated NF-κB and IL-4/STAT6 signaling, suppressed M1 and M2 macrophage infiltration and attenuated renal damage and fibrosis in UUO mice. NaHS treatment also suppressed NLRP3, NF-κB and IL-4/STAT6 activation in the obstructed kidneys. In conclusion, the therapeutic effects of H2S on UUO-induced renal injury and fibrosis are at least in part by inhibition of M1 and M2 macrophage infiltration. H2S suppresses NLRP3 activation and subsequently inactivates NF-κB and IL-4/STAT6 signaling, which may contribute to the anti-inflammatory and anti-fibrotic effects of H2S.