Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling
Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling
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DOI：
10.1152/ajprenal.00650.2012
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发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Ramesh, Ganesan
中科院分区：
文献类型：
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作者：
Ranganathan, Punithavathi;Jayakumar, Calpurnia;Ramesh, Ganesan
张建军，张建军，张建军，等。netrin-1近端小管特异性过表达通过抑制IL-6/STAT3信号传导抑制急性肾损伤诱导的间质纤维化和肾小球硬化。[J] .中国生物医学工程学报，2013,31(4):559 - 563。首次发表于2013年2月13日；doi: 10.1152 / ajprenal.00650.2012。-急性肾损伤引起的器官纤维化被认为是慢性肾脏疾病发展的主要危险因素，慢性肾脏疾病仍然是发达国家死亡的主要原因之一。然而，关于损伤后可能抑制纤维化反应的分子的知识是缺乏的。在急性肾损伤的缺血模型中，我们发现了netrin-1在调节间质纤维化中的新功能。在野生型和netrin-1转基因动物中，急性损伤后血清肌酐迅速升高。然而，与netrin-1转基因动物相比，野生型肾脏功能恢复缓慢，在3周后达到基线。组织学检查显示间质巨噬细胞浸润增加，广泛纤维化，毛细血管密度降低，肾小球硬化。假手术肾脏无IV型胶原和α -平滑肌肌动蛋白表达；然而，它们的表达在再灌注后2周显著增加，在再灌注后3周达到峰值。在近端小管上皮细胞中过表达netrin-1的转基因小鼠肾脏中，这些变化有所减少。纤维化与IL-6的表达增加和STAT3的广泛和慢性激活有关。IL-6在体内加重了野生型小鼠肾脏的纤维化，但在netrin-1转基因小鼠肾脏中无此作用；在体外缺氧再氧化的肾上皮细胞中，IL-6增加了胶原I的表达和STAT3的激活，这是由netrin-1抑制的。我们的数据表明，近端小管上皮细胞可能在间质纤维化中发挥重要作用，netrin-1可能是治疗肾纤维化的有效药物。
Ranganathan P, Jayakumar C, Ramesh G. Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling. Am J Physiol Renal Physiol 304: F1054-F1065, 2013. First published February 13, 2013; doi: 10.1152/ajprenal.00650.2012.-Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and alpha-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.