Renal denervation prevents long-term sequelae of ischemic renal injury.
Renal denervation prevents long-term sequelae of ischemic renal injury.
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肾脏神经阻止了缺血性肾损伤的长期后遗症。
DOI：
10.1038/ki.2014.300
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发表时间：
2015-02
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
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驱动肾缺血再灌注损伤后间质纤维化的信号仍不明确。交感神经激活甚至在慢性肾脏疾病的早期临床阶段也是明显的，并且与疾病的严重程度直接相关。肾神经在缺血再灌注损伤肾间质纤维化中的作用尚未研究。在雄性129 S1/SvImJ小鼠中，缺血再灌注损伤诱导肾小管间质纤维化，如损伤后4至16天的胶原沉积和促纤维化蛋白表达所示。缺血再灌注损伤后，白细胞内流、促炎蛋白表达、氧化应激、凋亡和细胞周期阻滞在G2/M期增强。损伤时或损伤后1天内的肾脏去神经支配改善了组织学，降低了促炎/促纤维化反应和细胞凋亡，并防止了肾脏中的G2/M细胞周期停滞。在去神经支配和缺血再灌注损伤诱导的肾脏中，用传入神经源性降钙素基因相关肽（CGRP）或传出神经源性去甲肾上腺素处理模拟神经支配，恢复炎症和纤维化，诱导G2/M期阻滞，并增强TGF-β1活化。使用相应的受体阻断剂阻断去甲肾上腺素或CGRP功能可防止这些作用。与体内研究一致，用去甲肾上腺素或CGRP处理诱导HK-2近端小管细胞的G2/M细胞周期阻滞，而针对其各自受体的拮抗剂阻止G2/M阻滞。因此，肾神经刺激是主要机制，肾神经衍生因子驱动上皮细胞周期停滞和炎症级联反应，导致缺血再灌注损伤后间质纤维化。
Signals that drive interstitial fibrogenesis after renal ischemia reperfusion injury remain undefined. Sympathetic activation is manifest even in the early clinical stages of chronic kidney disease and is directly related to disease severity. A role for renal nerves in renal interstitial fibrogenesis in the setting of ischemia reperfusion injury has not been studied. In male 129S1/SvImJ mice, ischemia reperfusion injury induced tubulointerstitial fibrosis as indicated by collagen deposition and profibrotic protein expression 4 to 16 days after the injury.. Leukocyte influx, proinflammatory protein expression, oxidative stress, apoptosis, and cell cycle arrest at G2/M phase were enhanced after ischemia reperfusion injury. Renal denervation at the time of injury or up to 1 day post-injury improved histology, decreased proinflammatory/profibrotic responses and apoptosis, and prevented G2/M cell cycle arrest in the kidney. Treatment with afferent nerve-derived calcitonin gene-related peptide (CGRP) or efferent nerve-derived norepinephrine in denervated and ischemia reperfusion injury-induced kidneys mimicked innervation, restored inflammation and fibrosis, induced G2/M arrest, and enhanced TGF-β1 activation. Blocking norepinephrine or CGRP function using respective receptor blockers prevented these effects. Consistent with the in vivo study, treatment with either norepinephrine or CGRP induced G2/M cell cycle arrest in HK-2 proximal tubule cells, whereas antagonists against their respective receptors prevented G2/M arrest. Thus, renal nerve stimulation is a primary mechanism and renal nerve-derived factors drive epithelial cell cycle arrest and the inflammatory cascade causing interstitial fibrogenesis after ischemia reperfusion injury.