Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis.
Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis.
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DOI：
10.1038/s41419-022-04910-w
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发表时间：
2022-05-31
影响因子：
9
通讯作者：
Zeng, Rui
中科院分区：
文献类型：
--
作者：
Xu, Huzi;Wang, Meng;Li, Yinzheng;Shi, Mengxia;Wang, Zheng;Cao, Chujin;Hong, Yu;Hu, Bin;Zhu, Han;Zhao, Zhi;Chu, Xiaoxin;Zhu, Fan;Deng, Xuan;Wu, Jianliang;Zhao, Fenfei;Guo, Jing;Wang, Yuxi;Pei, Guangchang;Zhu, Fengming;Wang, Xiaoyan;Yang, Juan;Yao, Ying;Zeng, Rui
损伤的肾小管上皮细胞(TECs)的代谢产物是否参与肾纤维化的研究还很少。在TEC损伤后，各种代谢物被释放出来，其中最有效的是三磷酸腺苷(ATP)，它是通过ATP通透通道释放的。在这些半突中，连接蛋白43(Cx43)是最常见的成员。然而，它在肾间质纤维化(RIF)中的作用还没有得到充分的研究。我们分析了梗阻性肾病患者和单侧输尿管梗阻(UUO)小鼠的肾脏样本。Cx43-KSP小鼠用于去除TECs中的Cx43。通过转录组学、代谢组学和单细胞测序多组学分析，探讨肾间质纤维化中肾小管Cx43、ATP和巨噬细胞之间的关系。梗阻性肾病患者和小鼠TECs中Cx43的表达均上调。在TEC中敲除Cx43或使用Cx43特异性抑制剂可以减少UUO诱导的小鼠炎症和纤维化。单细胞RNA测序表明，ATP特异性受体，包括P2rx4和P2rx7，主要分布于巨噬细胞。我们发现在UUO后，P2rx4或P2rx7阳性的巨噬细胞发生了下垂，而在体外，ATP直接诱导巨噬细胞下垂。给予UUO小鼠P2受体或P2X7受体阻断剂可抑制巨噬细胞松弛，并显示出与Cx43基因缺失类似程度的肾保护作用。此外，我们发现GAP 26(一种Cx43半通道抑制剂)和A-839977(一种焦磷脂受体的抑制剂)减轻了UUO诱导的纤维化，而BzATP(焦磷脂受体的激动剂)则加剧了纤维化。单细胞测序表明，嗜热巨噬细胞上调了CXCL10的释放，从而激活了肾内成纤维细胞。Cx43介导肾损伤时TECs释放ATP，引起肾小管周围巨噬细胞松弛，进而导致CXCL10释放，激活肾内成纤维细胞，加速肾纤维化。
Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites are released and among the most potent is adenosine triphosphate (ATP), which is released via ATP-permeable channels. In these hemichannels, connexin 43 (Cx43) is the most common member. However, its role in renal interstitial fibrosis (RIF) has not been fully examined. We analyzed renal samples from patients with obstructive nephropathy and mice with unilateral ureteral obstruction (UUO). Cx43-KSP mice were generated to deplete Cx43 in TECs. Through transcriptomics, metabolomics, and single-cell sequencing multi-omics analysis, the relationship among tubular Cx43, ATP, and macrophages in renal fibrosis was explored. The expression of Cx43 in TECs was upregulated in both patients and mice with obstructive nephropathy. Knockdown of Cx43 in TECs or using Cx43-specific inhibitors reduced UUO-induced inflammation and fibrosis in mice. Single-cell RNA sequencing showed that ATP specific receptors, including P2rx4 and P2rx7, were distributed mainly on macrophages. We found that P2rx4- or P2rx7-positive macrophages underwent pyroptosis after UUO, and in vitro ATP directly induced pyroptosis by macrophages. The administration of P2 receptor or P2X7 receptor blockers to UUO mice inhibited macrophage pyroptosis and demonstrated a similar degree of renoprotection as Cx43 genetic depletion. Further, we found that GAP 26 (a Cx43 hemichannel inhibitor) and A-839977 (an inhibitor of the pyroptosis receptor) alleviated UUO-induced fibrosis, while BzATP (the agonist of pyroptosis receptor) exacerbated fibrosis. Single-cell sequencing demonstrated that the pyroptotic macrophages upregulated the release of CXCL10, which activated intrarenal fibroblasts. Cx43 mediates the release of ATP from TECs during renal injury, inducing peritubular macrophage pyroptosis, which subsequently leads to the release of CXCL10 and activation of intrarenal fibroblasts and acceleration of renal fibrosis.
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影响因子：
5.6
作者：
Boengler K;Rohrbach S;Weissmann N;Schulz R
通讯作者：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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作者：
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作者：
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