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Role of Meprin A in Acute Kidney Injury

Meprin A 在急性肾损伤中的作用

基本信息

批准号：
8195620
负责人：
Gur Prasad Kaushal
金额：
--
依托单位：
CENTRAL ARKANSAS VETERANS HLTHCARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-10-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8195620
关键词：
Acute Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Address Admission activity Affect Animals Apical Binding Biological Assay Biological Markers Blood Circulation Blood Urea Nitrogen C3H/He Mouse CCL2 gene CD14 gene Cell membrane Cells Cisplatin Cleaved cell Collagen Type IV Creatinine Cytoplasm Dialysis procedure Disease Disintegrins Doctor of Philosophy Early Diagnosis Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Cells Excretory function Experimental Models Extracellular Matrix Extracellular Matrix Degradation Extracellular Matrix Proteins Family Fibronectins Generations Goals Gur Hemodialysis Immunofluorescence Immunologic In Vitro Infiltration Inflammation Inflammatory Injury Interleukin-1 Interleukin-1 beta Ischemia Kidney Kidney Diseases Kidney Failure Knockout Mice Laminin Leukocyte Trafficking Leukocytes Marrow Matrix Metalloproteinases Mediating Membrane Membrane Proteins Meprin Metalloproteases Molecular Mouse Strains Mus Na(+)-K(+)-Exchanging ATPase Nephrotoxic Nidogen Patients Peptide Hydrolases Peripheral Postoperative Period Process Production Proximal Kidney Tubules Publishing Rattus Recombinants Reperfusion Therapy Resistance Risk Risk Factors Role Serum Site Staining method Stains T-Lymphocyte Testing Therapeutic Intervention Time Tissues Tubular formation Urine Veterans Western Blotting base basolateral membrane brush border membrane chemokine clinically relevant cytokine in vivo in vivo Model inhibitor/antagonist insight kidney cortex member meprin A monocyte mortality mouse model nephrotoxicity new therapeutic target overexpression patient population prevent protective effect public health relevance response secretase urinary

项目摘要

Role of Meprin A in acute kidney injury Gur P. Kaushal, Ph.D. Project Summary Meprin A, a membrane-associated neutral metalloendoprotease, is highly expressed at the brush- border membranes of proximal tubules in the corticomedullary junction. The specific role of meprin A during acute kidney injury (AKI) is not fully understood. Our studies identified that meprin A is the major matrix-degrading protease in the rat kidney cortex capable of degrading the extracellular matrix (ECM) proteins including collagen IV, fibronectin, laminin, and nidogen in vitro. Our recently published and preliminary studies demonstrated that meprins are also capable of producing biologically active proinflammatory cytokine interleukin 1-¿ from its inactive proform and proteolytically processing chemotactic cytokine MCP-1, suggesting that meprins are also important in inflammation. Following ischemia-reperfusion (IR)- and cisplatin-induced AKI, meprin A is redistributed throughout the cytoplasm and extracellularly adhering toward the basolateral plasma membrane and the cleaved form of meprin A is excreted in the urine during AKI. These studies suggest that shedding and altered localization of meprin A in places other than the apical brush-border membranes may be deleterious in vivo in acute tubular injury. How membrane-associated meprin A is redistributed and shed is not known. Preliminary studies suggest that meprin A shedding may involve a member of the ADAM (a disintegrin and metalloproteinase) family. Using in vivo models of cisplatin- and IR-induced AKI, we demonstrated that actinonin, a potent inhibitor of meprin A inhibits meprin A in vivo and ameliorates acute kidney injury and meprin A-deficient C3H/He mice are resistant to AKI. Interestingly, we observed that nidogen and meprin-beta fragments, undetectable in the urine of normal mice, increased significantly before the rise in serum creatinine during the progression of IR- and cisplatin- induced AKI. Thus, a unique opportunity exists to further explore the role and mechanism of action of meprin A in AKI. We hypothesize that meprin A, with its enormous destructive potential, is detrimental to renal proximal tubules due to altered localization during AKI and that understanding its mechanism of action is important in protecting or reducing AKI. In addition, we hypothesize that meprin and nidogen fragments excreted during AKI will serve as important biomarkers for early detection of AKI. We will test these hypotheses through the following specific aims: 1. Examine the temporal relationship between meprin A redistribution, renal injury, leukocyte infiltration, meprin A shedding, and urinary excretion of meprin subunits during AKI using experimental models of IR and cisplatin nephrotoxicity. 2. Examine meprin A-mediated in vivo degradation products of nidogen during IR and cisplatin nephrotoxicity. 3. Determine the mechanisms of meprin A-mediated inflammatory effects and functional significance of meprin A inhibition after the onset of AKI. Understanding the underlying role of meprin A in AKI will provide insights for specific therapeutic interventions to prevent acute kidney injury.

甲氨蝶呤在急性肾损伤中的作用 Gur P. Kaushal博士项目摘要 Meprin A是一种膜相关中性金属内切蛋白酶，在刷状核高度表达。皮质髓质交界处近端小管的边缘膜。Meprin A的具体作用急性肾损伤（阿基）的发病机制尚未完全了解。我们的研究表明，meprin A是大鼠肾皮质中能够降解细胞外基质的主要基质降解蛋白酶 (ECM)蛋白质包括胶原IV、纤连蛋白、层粘连蛋白和巢蛋白。我们最近出版的初步研究表明，meprins也能够产生生物活性，促炎细胞因子白细胞介素1-â来自其无活性前体和蛋白水解加工趋化细胞因子MCP-1，表明meprins在炎症中也很重要。以下缺血-再灌注（IR）和顺铂诱导的阿基，meprin A在整个细胞质和细胞外粘附向基底外侧质膜和分裂的在阿基期间，甲氨蝶呤A的形式通过尿液排泄。这些研究表明，脱落和改变在除顶端刷状缘膜以外的地方定位meprin A可能是有害的在体内急性肾小管损伤中。膜相关的meprin A如何重新分布，而不是脱落知道的初步研究表明，meprin A脱落可能涉及ADAM的一个成员（a 去整合素和金属蛋白酶）家族。使用顺铂和IR诱导的阿基的体内模型，我们证明放线菌素，一种有效的meprin A抑制剂，在体内抑制meprin A，并改善急性肾损伤和meprin A缺陷的C3 H/He小鼠对阿基具有抗性。有趣的是，我们观察到巢蛋白和meprin-β片段，在正常小鼠的尿液中检测不到，在IR和顺铂进展期间血清肌酐升高前显著增加，诱发阿基。因此，存在一个独特的机会，进一步探讨的作用和作用机制，阿基中的甲氧苄氨嘧啶A。我们假设，具有巨大破坏潜力的甲氧苄氨嘧啶，由于阿基期间的定位改变而对肾近端小管有害，作用机制在保护或减少阿基中是重要的。此外，我们假设，在阿基期间排泄的meprin和巢蛋白片段将作为AKI早期的重要生物标志物。检测阿基。我们将通过以下具体目标来检验这些假设： 1.检查meprin A再分布、肾损伤、白细胞阿基期间meprin亚基浸润、meprin A脱落和尿排泄 IR和顺铂肾毒性模型。 2.在IR和顺铂期间检查meprin A介导的巢蛋白体内降解产物肾毒性 3.确定meprin A介导的炎症作用机制及功能意义阿基发作后的甲氨蝶呤A抑制。了解meprin A在阿基中的潜在作用将为特定的治疗方法提供见解。预防急性肾损伤。