Role of mitochondrial microRNAs (mitomiRs) in endogenous renal repair

线粒体 microRNA (mitomiRs) 在内源性肾修复中的作用

• 批准号: 10471652
• 负责人: Alfonso Eirin
• 金额: $ 10万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471652
• 关键词: 3-Dimensional; Address; Attenuated; Biogenesis; Biological Assay; Cell Nucleus; Cell physiology; Cells; Characteristics; Cytosine; Cytosol; Data; Deterioration; Development; Dioxygenases; Disease; Elderly; End stage renal failure; Enhancers; Enzymes; Epigenetic Process; Epithelial Cells; Exhibits; Family suidae; Fibrosis; Functional Imaging; Functional disorder; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Harvest; Histones; Hypertension; Imaging Techniques; Impairment; In Vitro; Inflammation; Infusion procedures; Injury to Kidney; Kidney; Kidney Diseases; Measures; Mediating; Methylation; MicroRNAs; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Nucleic Acid Regulatory Sequences; Oxidation-Reduction; Phenotype; Polyribonucleotide Nucleotidyltransferase; Population; Process; Production; Proliferating; Protein Import; Regulator Genes; Renal Artery Stenosis; Renal function; Ribonuclease III; Role; Structural defect; Structure; System; Techniques; Testing; Tubular formation; Untranslated RNA; cell injury; clinically relevant; experimental study; genome-wide; improved; in vivo; inhibitor/antagonist; injured; insight; kidney repair; migration; mortality; novel; novel strategies; oxidation; paracrine; porcine model; preservation; progenitor; promoter; protective effect; renal ischemia; repaired; reparative capacity; tool

Renal artery stenosis (RAS) remains a common cause of hypertension and end-stage renal disease in the elderly population, associated with increased morbidity and mortality. Recent data suggest that renal ischemia in RAS interferes with endogenous kidney repair mechanisms, such as CD133+/CD24+ scattered tubular-like cells (STCs), which can proliferate and their progeny re-differentiate into tubular epithelial cells to replace lost neighboring injured tubular cells. Our previous studies have shown that experimental RAS impairs the reparative capacity of swine STCs by inducing structural and functional abnormalities in their mitochondria. However, the processes underpinning RAS-induced STC mitochondrial damage remain unclear. Micro-RNAs (miRNAs) are non-coding RNA fragments that function as post-transcriptional regulators of gene expression. MiRNA genes are transcribed in the nucleus, which results in the production of pri- and pre- miRNA precursors, and subsequently mature miRNAs. Although most mature miRNAs are present in the cytosol, few miRNAs, known as ‘mitomiRs’, translocate to the mitochondrion to silence gene expression related to mitochondrial functions. Our preliminary data show that RAS increases expression of mitomiRs in swine STCs, associated with decreased expression of mitochondrial DNA (mtDNA) genes, and in turn mitochondrial structural abnormalities and dysfunction. Our pilot experiments also show that the promoters and enhancers of mitomiRs exhibit hyper 5-hydroxymethylation of cytosine (5hmC), an epigenetic mark generated by the oxidation of 5mC by the ten- eleven translocation methylcytosine dioxygenase (TET). Possibly, renal ischemia in RAS may alter mitomiR biogenesis and interfere with mitochondrial function in STCs. This might be partly mediated by epigenetic processes (5hmC) within mitomiR regulatory regions and/or increased import of mitomiRs into mitochondria. The working hypothesis underlying this proposal is that altered mitomiR expression in STCs underlies RAS-induced STC mitochondrial damage, blunting the paracrine function and capacity of STCs to preserve the post-stenotic kidney. Three specific aims will be pursued: Aim 1: will test whether increased mitomiR expression in RAS-STCs induces mitochondrial structural damage and dysfunction in STCs. Aim 2: will test whether RAS imposes epigenetic changes that increase mitomiR expression in STCs. Aim 3: will test whether aberrant mitomiR mitochondrial import contributes to STC dysfunction. Successful studies will provide novel insight into the vulnerability of this repair system and may contribute towards development of feasible clinically relevant tools for improving the utility and efficacy of kidney repair in renal disease.

肾动脉狭窄（RAS）仍然是高血压和终末期肾脏疾病的常见原因 老年人口，与发病率和死亡率的增加有关。最近的数据表明肾脏缺血 在RAS干扰内源性肾脏修复机制中，例如CD133+/CD24+散射管状样 细胞（STC），可以增殖，其后代重新分化为管状上皮细胞，以取代丢失 附近受伤的块茎细胞。我们以前的研究表明，实验RA会损害 通过诱导线粒体的结构和功能异常，猪STC的修复能力。 但是，尚不清楚RA​​S诱导的STC线粒体损伤的基础的过程尚不清楚。 微RNA（miRNA）是非编码RNA片段，起作用后的转录后调节剂 基因表达。 miRNA基因在细胞核中被转录，这导致产生pri-和pre-pre- miRNA前体，随后成熟的miRNA。尽管大多数成熟的miRNA都存在于 细胞质，很少的miRNA，称为“ mitomirs”，将其转移到线粒体到静音基因表达相关 线粒体功能。 我们的初步数据表明，RAS增加了与猪STC中的Mitomirs的表达，与 线粒体DNA（mtDNA）基因的发展表达，进而表达了线粒体结构异常 和功能障碍。我们的试点实验还表明，Mitomirs的启动子和增强子表现出超级 5HMC（5HMC）的5-羟基甲基化，这是通过十个氧化产生的表观遗传标记。 十一次转运甲基胞嘧啶二加氧酶（TET）。可能，RAS中的肾脏缺血可能会改变Mitomir STC中的生物发生和干扰线粒体功能。这可能部分是由表观遗传学介导的 Mitomir监管区域内的过程（5HMC）和/或Mitomirs进口到MitoMichondria中。 该提案的基础上的工作假设是STC中的Mitomir表达改变了 RAS诱导的STC线粒体损伤，使STC的旁分泌功能和能力钝化 保留静脉后的肾脏。将追求三个具体目标：目标1：将测试是否增加 RAS-STC中的Mitomir表达诱导STC中的线粒体结构损伤和功能障碍。目标2： 将测试RAS是否不可能表观遗传变化，从而增加STC中的Mitomir表达。目标3：将测试 Mitomir Mitomir线粒体进口是否有助于STC功能障碍。成功的研究将提供 对该维修系统脆弱性的新颖洞察力，可能有助于发展 临床相关的工具，用于提高肾脏疾病中肾脏修复的效用和效率。