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The Role of Hypobromous Acid in Renal Disease

次溴酸在肾脏疾病中的作用

基本信息

批准号：
9902413
负责人：
Gautam Bhave
金额：
$ 35.55万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902413
关键词：
Address Adult Affect Angiotensin II Animals Apoptosis Aristolochic Acids Attention Basement membrane Biochemical Biochemistry Bromine Cell Surface Receptors Cells Chemicals Chronic Kidney Failure Cicatrix Collagen Type IV Complex Cultured Cells Data Development Dialysis procedure Disease Drosophila genus End stage renal failure Epithelial Cells Equilibrium Exhibits Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis Generations Health Heme Hydrogen Peroxide Inflammation Inflammatory Infusion procedures Injury Injury to Kidney Kidney Kidney Diseases Knockout Mice Knowledge Lead Lipids Location Mass Spectrum Analysis Mechanical Stress Mechanics Mediating Modeling Mus Nephrectomy Nucleic Acids Oxidants Pathogenicity Pathway interactions Patients Peroxidases Phenotype Phosphotransferases Physiology Post-Translational Protein Processing Production Proteins Reactive Oxygen Species Role Signal Transduction Site Stretching Superoxides Testing Tissues Tubular formation Ureteral obstruction Work base cell behavior cell injury complex IV crosslink disorder prevention glomerular basement membrane hypobromous acid improved interstitial kidney cell kidney fibrosis loss of function mouse model novel overexpression oxidative damage perlecan peroxidasin pressure targeted treatment tissue injury

项目摘要

The excessive generation of reactive oxygen species (ROS) significantly contributes to maladaptive renal inflammation and fibrosis. While most attention has been directed towards superoxide, hydrogen peroxide (H2O2), and other ROS, our recent work has focused on hypobromous acid (HOBr) as an important ROS. Animal heme peroxidases produce HOBr using H2O2 and Br- as substrates. HOBr, a chemical cousin of bleach (HOCl), is a powerful oxidant capable of damaging proteins, lipids, and nucleic acids and typically promotes tissue injury. We recently discovered that an extracellular matrix (ECM) protein known as peroxidasin (Pxdn) also generates HOBr. Pxdn uses HOBr as an anabolic, reactive intermediate to form novel sulfilimine (S=N) cross- links in collagen IV, a prominent constituent of basement membranes (BM), such as glomerular BM (GBM). In Drosophila, we found that loss of Pxdn and sulfilimine cross-links compromised basement membrane and tissue integrity leading to larval lethality. However, Pxdn knock-out (KO) mice are viable but demonstrate reduced sulfilimine cross-links and BM strength. Based on this phenotype, we expected that unilateral ureteral obstruction (UUO) and increased intratubular pressures would lead to greater tubular BM stretch and mechanical stress on tubular cells in Pxdn KO mice. Consequently, Pxdn KO mice would exhibit increased renal inflammation and fibrosis. Paradoxically, Pxdn KO mice demonstrated less renal inflammation and fibrosis with diminished HOBr mediated oxidative damage. Based on these data, we hypothesize that Pxdn normally uses HOBr to cross-link collagen IV and support tissue integrity, but when dysregulated, Pxdn generates excessive HOBr leading to oxidative damage and tissue injury. To test this hypothesis, in Aim 1, we will determine whether Pxdn loss of function protects against renal injury that varies in extent of inflammation and localization contrasting glomerular and tubulointerstitial disease. Aim 2 will examine how HOBr alters renal cell behavior to promote tubulointerstitial fibrosis and inflammation, including the use of mass spectrometry to identify HOBr mediated oxidative modifications of proteins. In Aim 3, we will mechanistically address how Pxdn uses HOBr to cross-link collagen IV yet avoid collateral damage to other biomolecules. Taken together, this proposal aims to define a novel role for HOBr in renal inflammation and fibrosis. These studies hope to rationalize a strategy to target HOBr to treat chronic kidney disease.

活性氧（ROS）的过量产生是导致适应不良的重要原因