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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）：