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：
10295288
负责人：
Kelly Hyndman
金额：
$ 42.13万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10295288
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 Complement Factor B Coupled Data Development Disease Progression Electrolytes Endothelial Cells Endothelium Enzymes Epigenetic Process Epithelial Epithelial Cells 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 Lead 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 Testing Therapeutic Transforming Growth Factors 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.

概括急性肾损伤 (AKI) 发作与慢性肾损伤风险增加相关疾病（慢性肾病）；肾功能永久性丧失。 AKI 后，上皮细胞之间的串扰间质细胞对于肾脏愈合（适应性反应）至关重要，但如果时间延长会导致 CKD （适应不良）。有证据表明表观遗传修饰剂，例如组蛋白脱乙酰酶 (HDAC) 和 microRNA (miR) 可能会变得混乱，导致病理状况。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。差距在我们的知识存在于肾细胞类型特异性、HDAC 异构体依赖性机制中针对 AKI 的修复或慢性损伤。我们发现 AKI 后，HDAC1 显着肾皮质（包括成纤维细胞和周细胞）增加。利用诱导型成纤维细胞在特定 HDAC1 敲除 (KO) 小鼠中，我们发现成纤维细胞/周细胞 HDAC1 导致肌成纤维细胞活化和纤维化。 HDAC1 的一个潜在靶点可能是 miR-215-5p （miR215）。 miR215 因体内 HDAC 抑制而减少，并因肾脏中的 HDAC1 而增加成纤维细胞/周细胞。我们提供的数据表明成纤维细胞 miR215 具有促纤维化作用。从这些数据来看，我们建议检验以下假设：目标 1：检验 AKI 介导的假设纤维化依赖于成纤维细胞/周细胞 HDAC1 的激活。目标 2：测试假设 AKI 促进肾脏中 miR215 依赖性间质纤维化。这本 R01 中提出的实验将为表观遗传调控提供深层分子证据 AKI 后肾成纤维细胞/周细胞的变化，我们将确定动态表观遗传 CKD 过渡期间的图案化。同时使用有偏见和无偏见的方法将导致鉴定可能具有治疗价值的新途径，有助于减轻 AKI-CKD 过渡。