Epigenetic Regulation of Kidney Fibrosis following AKI

AKI 后肾脏纤维化的表观遗传调控

基本信息

批准号：
10625369
负责人：
Kelly Hyndman
金额：
$ 42.64万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625369
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Adverse event Atrophic Attenuated Bilateral Blood Vessels Blood flow Cardiac Cell Nucleus Cells Cessation of life Chromatin Chronic Chronic Kidney Failure Cicatrix Coupled Data Development Disease Progression Electrolytes Endothelial Cells Endothelium Enzymes Epigenetic Process Epithelial Cells Epithelium Fibroblasts Fibrosis Fostering Genes HDAC1 gene Histone Deacetylase Histone Deacetylase Inhibitor Immune In Vitro Injury Injury to Kidney Kidney Kidney Diseases Knock-out Knockout Mice Knowledge Liquid substance Mediating MicroRNAs Modeling Modification Molecular Myofibroblast Operative Surgical Procedures Outcome Pathologic Pathway interactions Patients Pattern Pericytes Protein Isoforms Proteins Publishing Renal function Reperfusion Injury Risk Signal Pathway Signal Transduction Source Structure of glomerular mesangium TGFB1 gene Testing Therapeutic Tubular formation Up-Regulation Ureteral obstruction attenuation beta catenin cell type differential expression epigenetic regulation epithelial repair experimental study glomerulosclerosis healing hypoperfusion in vivo interstitial interstitial cell kidney cell kidney cortex kidney fibrosis knock-down mouse model novel novel therapeutic intervention prevent repaired response transcriptome sequencing transcriptomics

项目摘要

SUMMARY Episodes of acute kidney injury (AKI) are associated with an increased risk for chronic kidney disease (CKD); a permanent loss of kidney function. Following AKI, crosstalk between epithelial and interstitial cells is critical for kidney healing (adaptive response) but if prolonged fosters CKD (maladaptive). Evidence suggests that epigenetic modifiers, such as histone deacetylases (HDACs) and microRNAs (miRs), can become deranged leading to pathological conditions. For example, activation of kidney HDACs following AKI is hypothesized to exacerbate injury; however, we and others have demonstrated that HDACs are also necessary for epithelial repair. A gap in our knowledge exists in the kidney cell type specific, HDAC isoform-dependent mechanisms of repair or chronic injury in response to AKI. We identified that following AKI, HDAC1 is significantly increased in the kidney cortex including in fibroblasts and pericytes. Utilizing inducible, fibroblast- specific HDAC1 knockout (KO) mice, we found that fibroblast/pericyte HDAC1 results in myofibroblast activation and fibrosis. One potential target of HDAC1 may be miR-215-5p (miR215). miR215 is reduced by in vivo HDAC inhibition, and is increased by HDAC1 in kidney fibroblast/pericyte cells. We provide data that fibroblast miR215 is profibrotic. From these data, we propose to test the following hypotheses: Aim 1: To test the hypothesis that AKI-mediated fibrosis is dependent on activation of fibroblast/pericyte cell HDAC1. Aim 2: To test the hypothesis that AKI promotes miR215 dependent interstitial fibrosis in the kidney. The experiments proposed in this R01 will provide deep molecular evidence of epigenetic regulation of the kidney fibroblast/pericytes following AKI and we will determine the dynamic epigenetic patterning during CKD transition. Using both biased and unbiased approaches will result in the identification of novel pathways that likely be of therapeutic value to help attenuate AKI-CKD transition.

概括急性肾脏损伤（AKI）发作与慢性肾脏风险增加有关疾病（CKD）；肾功能的永久丧失。跟随Aki，上皮之间的串扰和间质细胞对于肾脏愈合至关重要（自适应反应），但如果延长了fosters ckd （适应不良）。证据表明表观遗传修饰剂，例如组蛋白脱乙酰基酶（HDACS）和microRNA（mirs）可能会造成病理状况的毁灭。为了例如，假设AKI后肾脏HDAC的激活会加剧损伤。然而，我们和其他人已经证明，HDAC对于上皮修复也是必需的。差距我们的知识存在于特异性肾细胞类型的HDAC同工型依赖性机制中响应AKI的修复或慢性损伤。我们确定遵循AKI，HDAC1显着肾脏皮质的增加，包括成纤维细胞和周细胞。利用可诱导的成纤维细胞 - 特定的HDAC1敲除（KO）小鼠，我们发现成纤维细胞/周细胞HDAC1导致肌纤维细胞激活和纤维化。 HDAC1的一个潜在目标可以是miR-215-5p （mir215）。 MiR215通过体内HDAC抑制减少，并通过HDAC1在肾脏中增加成纤维细胞/周细胞。我们提供的数据表明成纤维细胞miR215是纤维化的。从这些数据，我们建议检验以下假设：目标1：测试AKI介导的假设纤维化取决于成纤维细胞/周细胞细胞HDAC1的激活。目标2：测试假设AKI促进了肾脏中依赖的MiR215依赖性间质纤维化。这在本R01中提出的实验将提供表观遗传调节的深层分子证据 AKI之后的肾脏成纤维细胞/周细胞，我们将确定动态表观遗传学 CKD过渡期间的图案。使用偏见和公正的方法将导致识别可能具有治疗价值的新途径，以帮助减轻AKI-CKD 过渡。