Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence.
Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence.
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DOI：
10.3389/fimmu.2021.823935
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发表时间：
2021
影响因子：
7.3
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Li Q;Deng Y;Liu L;Zhang C;Cai Y;Zhang T;Han M;Xu G
肾交感神经的持续过度激活被认为是肾纤维化的重要原因。受损肾脏中积累的衰老细胞具有代谢活动，并分泌大量促炎症因子，作为衰老相关分泌表型的一部分，导致慢性炎症和纤维化。目前尚不清楚肾交感神经是否通过调节细胞衰老来影响肾脏炎症和纤维化。因此，我们假设受损肾脏中的交感神经激活诱导细胞衰老，从而导致进行性肾脏炎症和纤维化。分别于单侧输尿管梗阻(UUO)和单侧输尿管缺血再灌注损伤(UIRI)模型建立前2d行肾神经切断。观察肾去神经对肾纤维化和细胞衰老的影响。在体外，去甲肾上腺素(NE)诱导肾近端小管上皮细胞系(TKPTS细胞)细胞衰老。用选择性α2A-肾上腺素能受体(α2A-AR)拮抗剂BRL44408和β-arrestin2siRNA抑制去甲肾上腺素诱导的细胞衰老。通过免疫印迹、免疫荧光、免疫细胞化学和涉及线粒体功能的功能分析，确定了一个显著改变的途径。在UUO和UIRI模型中，肾纤维化和细胞衰老显著增加，而去肾神经可部分逆转这一现象。在体外，NE通过激活α2A-AR诱导上皮细胞分泌促炎细胞因子，促进细胞衰老。重要的是，去甲肾上腺素在细胞衰老过程中的作用可被α2A-AR选择性拮抗剂和β-arrestin2(α2A-AR下游)siRNA阻断。肾交感神经激活和细胞衰老是肾纤维化发生发展过程中重要的神经代谢和神经免疫机制。肾交感神经递质NE作用于上皮细胞的α2A-AR，通过下游的β-arrestin2信号促进细胞衰老，这是一个潜在的肾脏纤维化的预防靶点。
Continuous overactivation of the renal sympathetic nerve is considered to be an important cause of renal fibrosis. Accumulated senescent cells in the damaged kidney have metabolic activities and secrete amounts of proinflammatory factors as part of the SASP (the senescence-associated secretory phenotype), which induce chronic inflammation and fibrosis. It is still unclear whether renal sympathetic nerves affect renal inflammation and fibrosis by regulating cellular senescence. Therefore, we hypothesize that sympathetic activation in the injured kidney induces cellular senescence, which contributes to progressive renal inflammation and fibrosis. Renal denervation was performed 2 days before the UUO (unilateral ureteral obstruction) and UIRI (unilateral ischemia-reperfusion injury) models. The effects of renal denervation on renal fibrosis and cellular senescence were observed. In vitro, cellular senescence was induced in renal proximal tubular epithelial cell lines (TKPTS cells) by treatment with norepinephrine (NE). The selective α2A-adrenergic receptor (α2A-AR) antagonists BRL44408 and β-arrestin2 siRNA, were administered to inhibit NE-induced cellular senescence. A significantly altered pathway was identified through immunoblotting, immunofluorescence, immunocytochemistry, and functional assays involved in mitochondrial function. Renal fibrosis and cellular senescence were significantly increased in UUO and UIRI models, which were partially reversed by renal denervation. In vitro, NE induced epithelial cells secreting proinflammatory cytokines and promoted cell senescence by activating α2A-AR. Importantly, the effects of NE during cellular senescence were blocked by α2A-AR selective antagonist and β-arrestin2 (downstream of α2A-AR) siRNA. Renal sympathetic activation and cellular senescence are important neurometabolic and neuroimmune mechanisms in the development of renal fibrosis. Renal sympathetic neurotransmitter NE acting on the α2A-AR of epithelial cells promotes cellular senescence through the downstream β-arrestin2 signaling, which is a potential preventive target for renal fibrosis.
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