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病的常见原因 老年人口，与发病率和死亡率增加有关。最近的数据表明，肾缺血。 RAS中干扰内源性肾脏修复机制，如CD133+/CD24+分散的管状 细胞（STC），可以增殖并且其后代重新分化为肾小管上皮细胞以替代丢失的肾小管上皮细胞 我们之前的研究表明，实验性 RAS 会损害邻近受损的肾小管细胞。 通过诱导线粒体结构和功能异常来增强猪 STC 的修复能力。 然而，RAS 诱导的 STC 线粒体损伤的过程仍不清楚。 Micro-RNA (miRNA) 是非编码 RNA 片段，可作为转录后调节因子 miRNA 基因在细胞核中转录，导致 pri- 和 pre- 的产生。 miRNA 前体，以及随后的成熟 miRNA，尽管大多数成熟 miRNA 都存在于 miRNA 中。 在细胞质中，少数 miRNA，称为“mitomiR”，易位至线粒体以沉默相关基因表达 线粒体功能。 我们的初步数据表明，RAS 增加了猪 STC 中 mitomiR 的表达，与 线粒体 DNA (mtDNA) 基因表达减少，进而导致线粒体结构异常 我们的初步实验还表明 mitomiR 的启动子和增强子表现出超强的功能。 胞嘧啶 (5hmC) 的 5-羟甲基化，是 5mC 被 10-羟甲基化所产生的表观遗传标记。 11 甲基胞嘧啶双加氧酶 (TET) 易位 RAS 中的肾缺血可能会改变 mitomiR。 生物发生并干扰 STC 中的线粒体功能，这可能部分是由表观遗传介导的。 mitomiR 调节区域内的过程（5hmC）和/或增加 mitomiR 进入线粒体。 该提议的工作假设是 STC 中 mitomiR 表达的改变是其基础 RAS 诱导的 STC 线粒体损伤，削弱了 STC 的旁分泌功能和能力 将追求三个具体目标： 目标 1：测试是否增加。 RAS-STC 中的 mitomiR 表达会诱导 STC 中的线粒体结构损伤和功能障碍。 将测试 RAS 是否会产生增加 STC 中 mitomiR 表达的表观遗传变化 目标 3：将测试。 异常的 mitomir 线粒体输入是否会导致 STC 功能障碍。成功的研究将提供这一点。 对这种修复系统的脆弱性的新见解可能有助于开发可行的 用于提高肾脏疾病中肾脏修复的实用性和功效的临床相关工具。

项目成果

Chronic kidney disease and left ventricular diastolic dysfunction (CKD-LVDD) alter cardiac expression of mitochondria-related genes in swine.

慢性肾病和左心室舒张功能障碍（CKD-LVDD）会改变猪线粒体相关基因的心脏表达。

• 发表时间: 2024-05
• 作者: Chade, Alejandro R;Sitz, Rhys;Kelty, Taylor J;McCarthy, Elizabeth;Tharp, Darla L;Rector, R Scott;Eirin, Alfonso
• 通讯作者: Eirin, Alfonso