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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：
8391547
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/8391547
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

DESCRIPTION (provided by applicant): 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 1-2 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.

描述（由申请人提供）： Meprin A 在急性肾损伤中的作用 Gur P. Kaushal 博士项目摘要 Meprin A 是一种膜相关的中性金属内蛋白酶，在皮质髓质交界处近端小管的刷状缘膜上高度表达。 meprin A 在急性肾损伤 (AKI) 过程中的具体作用尚不完全清楚。我们的研究发现，meprin A 是大鼠肾皮质中主要的基质降解蛋白酶，能够在体外降解细胞外基质 (ECM) 蛋白，包括 IV 型胶原、纤连蛋白、层粘连蛋白和巢蛋白。我们最近发表的初步研究表明，meprins 还能够从其无活性的原体产生具有生物活性的促炎细胞因子白细胞介素 1-2，并通过蛋白水解处理趋化细胞因子 MCP-1，这表明 meprins 在炎症中也很重要。缺血再灌注 (IR) 和顺铂诱导的 AKI 后，meprin A 在整个细胞质中重新分布，并在细胞外粘附到基底外侧质膜上，并且在 AKI 期间，meprin A 的裂解形式通过尿液排出。这些研究表明，在急性肾小管损伤中，除心尖刷状缘膜以外的地方meprin A的脱落和定位改变可能是有害的。膜相关 meprin A 如何重新分布和脱落尚不清楚。初步研究表明 meprin A 脱落可能涉及 ADAM（解整合素和金属蛋白酶）家族的成员。使用顺铂和IR诱导的AKI体内模型，我们证明了肌动蛋白（meprin A的有效抑制剂）在体内抑制meprin A并改善急性肾损伤，并且meprin A缺陷的C3H/He小鼠对AKI具有抵抗力。有趣的是，我们观察到，在 IR 和顺铂诱导的 AKI 进展过程中，正常小鼠尿液中检测不到的 nidogen 和 meprin-β 片段在血清肌酐升高之前显着增加。因此，存在进一步探索 meprin A 在 AKI 中的作用和作用机制的独特机会。我们假设 meprin A 具有巨大的破坏潜力，由于 AKI 期间定位的改变而对肾近曲小管有害，并且了解其作用机制对于保护或减少 AKI 非常重要。此外，我们假设 AKI 期间分泌的 meprin 和 nidogen 片段将作为 AKI 早期检测的重要生物标志物。我们将通过以下具体目标检验这些假设： 1. 使用 IR 和顺铂肾毒性实验模型，检查 AKI 期间 meprin A 重新分布、肾损伤、白细胞浸润、meprin A 脱落和 meprin 亚基尿排泄之间的时间关系。 2. 检查 IR 和顺铂肾毒性过程中 meprin A 介导的 nidogen 体内降解产物。 3.确定meprin A介导的炎症效应的机制以及AKI发作后meprin A抑制的功能意义。了解 meprin A 在 AKI 中的潜在作用将为预防急性肾损伤的具体治疗干预提供见解。