Role of Meprins in Ischemia Reperfusion induced renal injury

Meprins 在缺血再灌注引起的肾损伤中的作用

基本信息

批准号：
8887348
负责人：
Elimelda Moige Ongeri
金额：
$ 10.69万
依托单位：
NORTH CAROLINA AGRI & TECH ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887348
关键词：
Actins Acute Kidney Failure Affect Catalytic Domain Cell Line Cell physiology Cells Cellular Morphology Cleaved cell Complementary DNA Complex Confocal Microscopy Cyclic AMP-Dependent Protein Kinases Cytoskeletal Proteins Cytoskeleton Data Development Elements Extracellular Matrix Extracellular Matrix Proteins Fibronectins Gene Expression Genes Goals Hypoxia Immunohistochemistry In Vitro Injury Integrins Ischemia Kidney Kidney Failure Knockout Mice Laminin Location Mass Spectrum Analysis Mediating Meprin Metalloproteases Morbidity - disease rate Mouse Strains Mus Outcome Pathology Pathway interactions Play Protein Isoforms Proteins Proteomics Proximal Kidney Tubules Recombinants Reperfusion Injury Reperfusion Therapy Resources Role Signal Pathway Signal Transduction Signaling Molecule Structure Tail Testing Tight Junctions Work brush border membrane cellular microvillus in vitro Model in vivo inhibitor/antagonist insight kidney cell mortality occludin prevent renal ischemia response therapy development villin

项目摘要

DESCRIPTION (provided by applicant): Ischemia reperfusion (IR) induced renal injury causes acute renal failure and is associated with high morbidity and mortality rates. The cellular mechanisms underlying IR renal injury are not known. Meprins, metalloproteases that are abundantly expressed in the brush border membranes (BBM) of proximal kidney tubules, have been implicated in the pathology of IR. Mice strains with lower levels of meprins develop less renal injury when subjected to IR. Meprin inhibitors and targeted disruption of the meprin gene both protect mice from IR induced renal injury. We recently demonstrated that meprins cleave actin and villin, the key components of the proximal tubule cell cytoskeleton, suggesting that the observed renal injury is in part due to degradation of cytoskeletal proteins. Meprin B also cleaves the catalytic subunit of protein kinase A (PKA), a protein that modulates many cellular signaling pathways. OS-9, a protein involved in the hypoxia response, has been shown to interact with the carboxyl-terminal tail of meprin. However, it is not known if OS-9 is a meprin substrate, and whether interaction between OS-9 and meprin plays a role in the pathology of IR induced renal injury. The broad long term goal of this project is to elucidate the cellular mechanisms responsible for IR induced kidney injury, and facilitate development of therapies to prevent IR associated renal failure. The central hypothesis is that meprins play a key role in the injuries observed in renal IR. This is in part due to cleavage of cytoskeletal proteins (such as villin and actin), proteins present in tight junction complexes, and extracellular matrix (ECM) proteins. Meprins may also play an indirect role by cleaving proteins that modulate specific signaling pathways (such as PKA and OS-9) and thus impacting expression of genes driven by these pathways. The proposed studies will use meprin knockout mice and proteomic approaches to identify meprin associated proteins that play a role in IR and elucidate underlying cellular mechanisms. The central hypothesis will be tested by pursuing the following three specific aims: (i) to identify meprin-associated proteins that play a role in IR induced renal injuy, (ii) to determine the role of meprins in cytoskeletal remodeling associated with IR induced renal injury, (iii) to determine if interactions between meprins and cell signaling molecules play a role in IR induced kidney injury. Results from the proposed studies are expected to have an important positive impact because elucidating the mechanisms underlying IR induced renal injury will facilitate development of therapies for preventing acute renal failure due to IR.

描述（由申请人提供）：缺血再灌注（IR）诱导的肾损伤会导致急性肾衰竭，并与高发病率和死亡率相关。 IR 肾损伤的细胞机制尚不清楚。 Meprins 是一种在近端肾小管刷状缘膜 (BBM) 中大量表达的金属蛋白酶，与 IR 的病理学有关。具有较低水平 meprins 的小鼠品系在接受 IR 时发生的肾损伤较少。 Meprin 抑制剂和 Meprin 基因的靶向破坏均可保护小鼠免受 IR 引起的肾损伤。我们最近证明，meprins 会裂解肌动蛋白和绒毛蛋白（近端肾小管细胞骨架的关键成分），这表明观察到的肾损伤部分是由于细胞骨架蛋白的降解所致。 Meprin B 还可裂解蛋白激酶 A (PKA) 的催化亚基，PKA 是一种调节许多细胞信号传导途径的蛋白质。 OS-9 是一种参与缺氧反应的蛋白质，已被证明与 meprin 的羧基末端尾部相互作用。然而，尚不清楚 OS-9 是否是 meprin 底物，以及 OS-9 和 meprin 之间的相互作用是否在 IR 诱导的肾损伤病理学中发挥作用。该项目的长期目标是阐明 IR 诱导肾损伤的细胞机制，并促进开发预防 IR 相关肾衰竭的疗法。中心假设是 meprins 在肾 IR 观察到的损伤中发挥着关键作用。这部分是由于细胞骨架蛋白（例如绒毛蛋白和肌动蛋白）、紧密连接复合物中存在的蛋白以及细胞外基质（ECM）蛋白的裂解所致。 Meprins 还可能通过裂解调节特定信号传导途径（例如 PKA 和 OS-9）的蛋白质来发挥间接作用，从而影响由这些途径驱动的基因的表达。拟议的研究将使用 meprin 敲除小鼠和蛋白质组学方法来鉴定在 IR 中发挥作用的 meprin 相关蛋白并阐明潜在的细胞机制。将通过追求以下三个具体目标来检验中心假设：(i) 鉴定在 IR 诱导的肾损伤中发挥作用的 meprins 相关蛋白，(ii) 确定 meprins 在与 IR 诱导的肾损伤相关的细胞骨架重塑中的作用损伤，(iii) 确定 meprins 和细胞信号分子之间的相互作用是否发挥作用 IR 引起的肾损伤。拟议研究的结果预计将产生重要的积极影响，因为阐明 IR 引起的肾损伤的机制将有助于开发预防 IR 引起的急性肾衰竭的疗法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Erratum to "Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in Mice with STZ-Induced Type 1 Diabetes".

DOI：
10.1155/2018/2462697
发表时间：
2018
期刊：
Journal of diabetes research
影响因子：
4.3
作者：
Bylander JE;Ahmed F;Conley SM;Mwiza JM;Moige E
通讯作者：
Moige E

In vitro production of testosterone and plasma levels of luteinising hormone, testosterone and cortisol in male rats treated with heptachlor.

用七氯处理的雄性大鼠体内睾酮的体外产生以及黄体生成素、睾酮和皮质醇的血浆水平。

DOI：
10.1016/s0742-8413(97)00104-7
发表时间：
1997
期刊：
Comparative biochemistry and physiology. Part C, Pharmacology, toxicology & endocrinology
影响因子：
0
作者：
Wango,EO;Onyango,DW;Odongo,H;Okindo,E;Mugweru,J
通讯作者：
Mugweru,J