The cytohesin guanosine exchange factors (GEFs) are required to promote HGF-mediated renal recovery after acute kidney injury (AKI) in mice.
The cytohesin guanosine exchange factors (GEFs) are required to promote HGF-mediated renal recovery after acute kidney injury (AKI) in mice.
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DOI：
10.14814/phy2.12442
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发表时间：
2015-06
影响因子：
2.5
通讯作者：
Santy LC
中科院分区：
文献类型：
--
作者：
Reviriego-Mendoza MM;Santy LC
目前缺乏对住院患者急性肾损伤（阿基）的治疗和预防措施，导致死亡率增加至80%，医疗费用增加。此外，如果没有得到适当的修复，阿基幸存者可能会出现纤维化和长期肾损伤。肾损伤和修复的分子方面仍然不确定。肝细胞生长因子（HGF）通过诱导肾小管上皮细胞的存活和迁移以重新填充裸露的肾小管区域来促进受损肾脏的恢复。HGF刺激的肾上皮细胞迁移需要ADP-核糖基化因子6（Arf 6）和Rac 1通过细胞粘连素家族的Arf-鸟嘌呤-核苷酸交换因子（GEFs）在体外激活。我们使用缺血再灌注损伤（IRI）小鼠模型来分析调节该信号通路对肾脏恢复的影响。我们用HGF、细胞粘连蛋白抑制剂SecinH 3或两者的组合治疗IRI小鼠。如前所述，HGF治疗促进了肾功能的快速改善，如肌酐（Cre）和血尿素氮（BUN）水平所证明的。相反，SecinH 3和HGF的同时治疗阻断了HGF促进肾恢复的能力。免疫组化显示，HGF治疗促进肾小管结构的恢复，并具有增强的活性，GTP结合的Arf 6和GTP-Rac 1的水平。然而，SecinH 3处理导致GTP-Arf 6和GTP-Rac 1水平与HGF处理的IRI小鼠的肾切片相比显著降低。此外，SecinH 3抵消了HGF的肾修复作用。我们的研究结果支持这样的结论，即细胞粘连素的功能是必要的HGF刺激肾IRI修复。
The lack of current treatment and preventable measures for acute kidney injury (AKI) in hospitalized patients results in an increased mortality rate of up to 80% and elevated health costs. Additionally, if not properly repaired, those who survive AKI may develop fibrosis and long-term kidney damage. The molecular aspects of kidney injury and repair are still uncertain. Hepatocyte growth factor (HGF) promotes recovery of the injured kidney by inducing survival and migration of tubular epithelial cells to repopulate bare tubule areas. HGF-stimulated kidney epithelial cell migration requires the activation of ADP-ribosylation factor 6 (Arf6) and Rac1 via the cytohesin family of Arf-guanine-nucleotide exchange factors (GEFs), in vitro. We used an ischemia and reperfusion injury (IRI) mouse model to analyze the effects of modulating this signaling pathway on kidney recovery. We treated IRI mice with either HGF, the cytohesin inhibitor SecinH3, or a combination of both. As previously reported, HGF treatment promoted rapid improvement of kidney function as evidenced by creatinine (Cre) and blood urea nitrogen (BUN) levels. In contrast, simultaneous treatment with SecinH3 and HGF blocks the ability of HGF to promote kidney recovery. Immunohistochemistry showed that HGF treatment promoted recovery of tubule structure, and had enhanced levels of active, GTP-bound Arf6 and GTP-Rac1. SecinH3 treatment, however, caused a dramatic decrease in GTP-Arf6 and GTP-Rac1 levels when compared to kidney sections from HGF-treated IRI mice. Additionally, SecinH3 counteracted the renal reparative effects of HGF. Our results support the conclusion that cytohesin function is required for HGF-stimulated renal IRI repair.