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Proximal tubule Kim-1 expression modulates acute and chronic kidney injury

近端小管 Kim-1 表达调节急性和慢性肾损伤

基本信息

批准号：
8699766
负责人：
Craig Robert Brooks
金额：
$ 15.74万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699766
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Apoptotic Area Autoantibodies Autoimmunity Autophagocytosis Birth Caspase Cell Death Cells Cellular biology Chronic Chronic Kidney Failure Clinical Cytoprotection Data Diagnostic Endocytosis Epithelial Cells Family member Genetic Goals Immune response Immunology Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Ischemia Kidney Knock-out Knowledge Laboratories Ligand Binding Ligands Light Major Histocompatibility Complex Mediating Mentors Mitochondria Modeling Morbidity - disease rate Mucins Mus Nephrotoxic Outcome Pathology Pathway interactions Patients Phagocytes Phagocytosis Phosphatidylserines Phosphorylation Production Proteins Proximal Kidney Tubules Renal function Research Research Personnel Resistance Resolution Role Signal Pathway Testing Therapeutic Training Transgenic Mice Transgenic Organisms Tubular formation Tyrosine Phosphorylation cell injury cell type cytokine glomerular filtration immunoregulation in vivo injured mortality mouse model multidisciplinary mutant novel overexpression oxidized lipid oxidized low density lipoprotein prevent protective effect protein function public health relevance rat KIM-1 protein response scavenger receptor skills therapeutic target tool uptake

项目摘要

DESCRIPTION (provided by applicant): Renal proximal tubule epithelial cells (PTCs) are vital to the function of the kidney and are also integral to the pathology of the injured kidney. They are the most sensitive cell type in the kidney to ischemia and nephrotoxic insults. PTCs are also involved in the signaling pathways governing inflammation, such as secretion of cytokines and presentation of antigens to MHC II, and resolution following injury. We have identified Kim-1 as the most highly upregulated protein in injured PTCs. While Kim-1 has been shown to be a promising diagnostic tool for detecting kidney injury, the pathobiological function of this protein and its role in kidney injury are not known. Our preliminary data suggest that Kim-1-mediated phagocytosis induces autophagy and cytoprotection in PTCs following acute kidney injury. Prolonged expression of Kim-1, however, leads to inflammation and tubule damage, mimicking chronic kidney disease. Furthermore, we have found that Kim-1-mediated phagocytosis and autophagy induction leads to antigen presentation, and depending on the ligands and duration of Kim-1 expression, the outcome could be pro or anti-inflammatory. Therefore, I propose that Kim-1 mediated phagocytosis of apoptotic cells in AKI induces autophagy, which leads to immune modulation through MHC presentation. In AKI, the consequences of autophagy are cytoprotective while in chronic states where the PT lumen contains other Kim-1 ligands, such as oxidized lipids, and fewer apoptotic cells, Kim-1 mediated uptake of these ligands induces a pro-inflammatory, profibrotic response. This is a multidisciplinary study that will build on my knowledge and research skills in cell biology and extend my training into novel areas such as immunology and mouse genetics. To address this hypothesis we will first examine if the protective effect of Kim-1 in AKI is due to its autophagy induction. We will test if Kim- 1-induced autophagy is protective against various insults. Then we will examine if mice expressing a Kim-1 phaogocytosis deficient mouse has an altered autophagic response. To understand how Kim-1 regulates autophagy, the role of Kim-1 phosphorylation and its interaction with GABARAP (an LC3 family member) in autophagy induction. Second, we will determine if Kim-1-mediated endocytosis contributes to chronic injury. Unlike phagocytosis of apoptotic cells, endocytosis of ligands such as ox-LDL, leads to mitochondrial fragmentation and caspase activation. We will test if transgenic overexpression of wt Kim-1 or Kim-1 mutant which can take up ox-LDL but not apoptotic cells leads to greater injury than overexpression of a mutant which takes up neither apoptotic cells or ox-LDL. We will then test if the mitochondrial fragmentation observed following Kim-1-mediated uptake of ox-LDL is due to activation of the mitochondrial fission pathway and whether inhibiting mitochondrial fragmentation prevents cellular injury induced by Kim-1-mediated endocytosis of ox-LDL. Finally, we will examine if Kim-1-induced autophagy modulates the PTC immune response through MHC presentation. We will examine the role of MHC II presentation in AKI and CKD through conditional knockout of MHC II. We will then determine if mice expressing Kim-1 phagocytosis deficient mutant have an altered immune response and autoantibody production. As proximal tubule cells also express co-stimulatory and co-inhibitory factors, we will test if Kim-1 induced autophagy modulates the expression of these factors. The findings from this study will shed light on the role of Kim-1 in acute and chronic kidney injury, as well as highlight the potential therapeutic benefits of modulating Kim-1 function in kidney injury.

描述（由申请人提供）：肾近端小管上皮细胞（ptc）对肾脏的功能至关重要，也是损伤肾脏病理的组成部分。它们是肾脏中对缺血和肾毒性损伤最敏感的细胞类型。ptc还参与控制炎症的信号通路，如细胞因子的分泌和抗原向MHC II的呈递，以及损伤后的消退。我们已经确定，在受损的ptc中，Kim-1是最高度上调的蛋白。虽然Kim-1已被证明是一种很有前途的诊断工具，用于检测肾损伤，该蛋白的病理生物学功能