Epigenetic Regulation of Kidney Fibrosis following AKI

AKI 后肾脏纤维化的表观遗传调控

• 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
• 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

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.

总结 急性肾损伤（阿基）的发作与慢性肾功能衰竭的风险增加有关。 慢性肾脏病（CKD）;肾功能的永久性丧失。阿基后，上皮细胞之间的串扰 和间质细胞是至关重要的肾脏愈合（适应性反应），但如果长期促进慢性肾病 （适应不良）。有证据表明，表观遗传修饰剂，如组蛋白脱乙酰酶， HDAC（HDAC）和microRNA（miR）可以变得紊乱，导致病理状况。为 例如，假设阿基后肾脏HDAC的激活会加重损伤;然而， 我们和其他人已经证明HDAC也是上皮修复所必需的。中的间隙 我们的知识存在于肾细胞类型特异性，HDAC亚型依赖性机制中， 修复或慢性损伤，以应对阿基。我们发现，在阿基后，HDAC 1显著降低， 在肾皮质包括成纤维细胞和周细胞中增加。利用可诱导的成纤维细胞- 特异性HDAC 1敲除（KO）小鼠，我们发现成纤维细胞/周细胞HDAC 1导致 肌成纤维细胞活化和纤维化。HDAC 1的一个潜在靶点可能是miR-215- 5 p （miR215）。miR 215通过体内HDAC抑制而减少，并且通过肾脏中的HDAC 1而增加 成纤维细胞/周细胞。我们提供了成纤维细胞miR 215是促纤维化的数据。从这些数据来看， 目的1：为了验证AKI介导的细胞凋亡的假设， 纤维化依赖于成纤维细胞/周细胞HDAC 1的活化。目标2：测试 阿基促进肾脏中miR 215依赖性间质纤维化的假设。的 本R 01中提出的实验将为表观遗传调控提供深入的分子证据 阿基后肾脏成纤维细胞/周细胞的动态表观遗传学变化， CKD过渡期的模式化。使用有偏和无偏的方法将导致 鉴定可能具有治疗价值的新途径以帮助减轻AKI-CKD 过渡