The BMP-7-Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury.
The BMP-7-Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury.
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DOI：
10.1016/j.juro.2011.01.034
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Austin PF
中科院分区：
文献类型：
--
作者：
Manson SR;Niederhoff RA;Hruska KA;Austin PF
尿路梗阻引起输尿管肾积水，需要手术干预，以防止发展为永久性肾损伤。虽然许多研究都集中在肾损伤的发展，在这里，我们检查的分子机制，促进肾恢复后纠正梗阻。使用输尿管梗阻的可逆小鼠模型来检查梗阻诱导的损伤后肾恢复期间的BMP-7和TGF-β信号传导途径。使用标准分子技术进行分析，包括RT-PCR、ELISA、免疫印迹和免疫共沉淀。我们发现，梗阻纠正后BMP-7的上调抑制了TGF-β依赖性促纤维化途径，这是肾损伤发病机制的核心。BMP-7的抑制作用部分地通过其下游靶蛋白Smad 1、Smad 5和Smad 8的活化介导，所述下游靶蛋白Smad 1、Smad 5和Smad 8抑制TGF-β依赖性Smad蛋白的活性，并进而抑制TGF-β依赖性基因的表达。最后，在肾恢复过程中BMP-7-Smad 1/5/8通路的激活促进了肾结构的恢复和梗阻纠正后肾纤维化的消退。总之，这些发现表明，BMP-7-Smad 1/5/8通路促进阻塞诱导的损伤后肾脏的修复。因此，BMP-7通路代表了在治疗阻塞诱导的肾损伤期间刺激肾的先天修复机制的重要治疗靶标。
Urinary tract obstruction causes hydroureteronephrosis and requires surgical intervention to prevent the development of permanent renal injury. While many studies have focused on the development of renal injuries, here we examine the molecular mechanisms that promote renal recovery following the correction of obstruction. A reversible murine model of ureteral obstruction was used to examine the BMP-7 and TGF-β signaling pathways during renal recovery following obstruction-induced injury. Analysis was conducted using standard molecular techniques including RT-PCR, ELISA, immunoblotting, and co-immunoprecipitation. We found that the upregulation of BMP-7 following the correction of obstruction inhibits TGF-β-dependent pro-fibrotic pathways that are central to the pathogenesis of renal injury. The inhibitory effects of BMP-7 are mediated, in part, by the activation of its downstream target proteins, Smad1, Smad5, and Smad8, which suppress the activity of TGF-β-dependent Smad proteins and, in turn, inhibit the expression of TGF-β-dependent genes. Finally, the activation of the BMP-7–Smad1/5/8 pathway during renal recovery promotes the restoration of renal architecture and resolution of fibrosis in the kidney following the correction of obstruction. Together, these findings demonstrate that the BMP-7–Smad1/5/8 pathway promotes the repair of the kidney following obstruction-induced injury. Accordingly, the BMP-7 pathway represents an important therapeutic target to stimulate the innate repair mechanisms of the kidney during the treatment of obstruction-induced renal injuries.
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