Gpr97 Exacerbates AKI by Mediating Sema3A Signaling
Gpr97 Exacerbates AKI by Mediating Sema3A Signaling
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Gpr97 通过介导 Sema3A 信号传导加剧 AKI
DOI：
10.1681/asn.2017080932
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发表时间：
2018-05-01
影响因子：
13.6
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Fang, Wei;Wang, Ziying;Yi, Fan
研究背景G蛋白偶联受体（GPCRs）参与多种生理功能，其中一些GPCRs在肾功能调节中具有重要的生理和病理生理作用。我们研究了一个新发现的粘附GPCR家族成员Gpr 97在阿基中的作用。方法在Gpr 97缺陷小鼠中通过缺血再灌注或顺铂治疗诱导阿基。我们评估了这些模型中的肾损伤和急性肾小管坏死患者的组织学检查，我们进行了微阵列分析和体外试验，以确定Gpr 97 function.Results的分子机制，Gpr 97是上调的肾脏与阿基小鼠和活检证实的急性肾小管坏死患者与健康对照组相比。在阿基模型中，Gpr 97缺陷型小鼠的肾损伤和炎症明显少于野生型小鼠。Gpr 97缺陷还减弱了AKI诱导的脑信号蛋白3A（Sema 3A）的表达，Sema 3A是肾损伤的潜在早期诊断生物标志物。在NRK-52 E细胞中进行氧-葡萄糖剥夺，siRNA介导的Gpr 97敲低进一步增加了生存素和磷酸化STAT 3的表达，并减少了Toll样受体4的表达。与重组小鼠Sema 3A蛋白的共治疗抵消了这些影响。最后，包括电泳迁移率变动分析和荧光素酶报告基因分析在内的其他体内和体外研究表明，Gpr 97缺陷减弱了缺血再灌注诱导的RNA结合蛋白人抗原R的表达，该蛋白在转录后调节Sema 3A的表达。并且在多个水平上对Gpr 97介导的Sema 3A信号传导进行药理学靶向可以提供用于治疗阿基的新方法。
Background G protein-coupled receptors (GPCRs) participate in a variety of physiologic functions, and several GPCRs have critical physiologic and pathophysiologic roles in the regulation of renal function. We investigated the role of Gpr97, a newly identified member of the adhesion GPCR family, in AKI.Methods AKI was induced by ischemia-reperfusion or cisplatin treatment in Gpr97-deficient mice. We assessed renal injury in these models and in patients with acute tubular necrosis by histologic examination, and we conducted microarray analysis and in vitro assays to determine the molecular mechanisms of Gpr97 function.Results Gpr97 was upregulated in the kidneys from mice with AKI and patients with biopsy-proven acute tubular necrosis compared with healthy controls. In AKI models, Gpr97-deficient mice had significantly less renal injury and inflammation than wild-type mice. Gpr97 deficiency also attenuated the AKI-induced expression of semaphorin 3A (Sema3A), a potential early diagnostic biomarker of renal injury. In NRK-52E cells subjected to oxygen-glucose deprivation, siRNA-mediated knockdown of Gpr97 further increased the expression of survivin and phosphorylated STAT3 and reduced toll-like receptor 4 expression. Cotreatment with recombinant murine Sema3A protein counteracted these effects. Finally, additional in vivo and in vitro studies, including electrophoretic mobility shift assays and luciferase reporter assays, showed that Gpr97 deficiency attenuates ischemia-reperfusion-induced expression of the RNA-binding protein human antigen R, which post-transcriptionally regulates Sema3A expression.Conclusions Gpr97 is an important mediator of AKI, and pharmacologic targeting of Gpr97-mediated Sema3A signaling at multiple levels may provide a novel approach for the treatment of AKI.