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: 10583380
• 负责人: Alfonso Eirin
• 金额: $ 47.2万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583380
• 关键词: 3-Dimensional; Address; Attenuated; Bioenergetics; Biogenesis; Cell Nucleus; Cell physiology; Cells; Characteristics; Cytosine; Cytosol; DNA; Data; Deterioration; Development; Dioxygenases; Down-Regulation; Elderly; End stage renal failure; Enhancers; Enzymes; Epigenetic Process; Epithelial Cells; Event; Exhibits; Family suidae; Fibrosis; Functional Imaging; Functional disorder; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Harvest; Histones; Homeostasis; Hypertension; Imaging Techniques; Impairment; In Vitro; Inflammation; Infusion procedures; Injury to Kidney; Kidney; Kidney Diseases; Measures; Methylation; MicroRNAs; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Nuclear; Oxidation-Reduction; Phenotype; Pilot Projects; Polyribonucleotide Nucleotidyltransferase; Population; Process; Production; Proliferating; Protein Import; Regulator Genes; Renal Artery Stenosis; Renal function; Role; Structural defect; Structure; System; Techniques; Testing; Tubular formation; alpha ketoglutarate; cell injury; clinically relevant; cofactor; experimental study; genome-wide; improved; in vivo; inhibitor; injured; insight; kidney repair; miRNA expression profiling; migration; mortality; novel; novel strategies; oxidation; paracrine; porcine model; posttranscriptional; 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) 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 the mitomiR-181c in swine STCs associated with decreased expression of its mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoded mitochondrial gene targets, and in turn mitochondrial structural abnormalities and dysfunction. In addition, we found that the promoters and enhancers of the miR-181c gene (MIR181C) exhibit hyper 5-hydroxymethylation of cytosine (5hmC), an epigenetic mark generated by the oxidation of 5mC by the ten-eleven translocation methylcytosine dioxygenase (TET) enzyme. Excitingly, in our pilot studies anti-miR-181c, the TET inhibitor Bobcat339, and inhibitors of the mitomiR import proteins ameliorate mitochondrial damage in swine-STCs. Our central hypothesis is thus that altered miR-181c 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 miR-181c expression in RAS-STCs induces mitochondrial structural damage and dysfunction in STCs. Aim 2: will test whether RAS imposes epigenetic changes that increase miR-181c expression in STCs. Aim 3: will test whether aberrant miR-181c 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）充当基因表达的转录后调节剂。 miRNA基因是 在细胞核中转录，从而导致pri-miRNA前体的产生，然后 尽管大多数成熟的miRNA都存在于细胞质中，但很少有miRNA，称为“ mitomirs”， 转移到线粒体到与线粒体功能有关的沉默基因表达。 我们的初步数据表明，RAS在相关的猪STC中增加了Mitomir-181c的表达 其线粒体DNA（mtDNA）和核DNA（NDNA）编码线粒体的表达改善 基因靶标，进而线粒体结构异常和功能障碍。此外，我们发现 miR-181c基因（miR181c）的启动子和增强子暴露于胞嘧啶的超5-羟基甲基化 （5HMC），这是通过十个易位甲基胞霉素氧化5MC产生的表观遗传标记 二氧酶（TET）酶。令人兴奋的是，在我们的试点研究中，抗MIR-181C，TET抑制剂Bobcat339和 Mitomir进口蛋白的抑制剂可以改善猪-STC中的线粒体损伤。 因此，我们的中心假设是改变了STC中的miR-181c表达是RAS诱导的STC的基础 线粒体损伤，使STC的旁分泌功能和能力钝化以保留后 狭窄的肾脏。将追求三个具体目标：目标1：将测试miR-181c表达是否增加 在RAS-STC中，STC诱导线粒体结构损伤和功能障碍。 AIM 2：将测试RAS是否 施加表观遗传变化，增加了STC中miR-181c的表达。目标3：将测试是否异常 miR-181c线粒体导入导致STC功能障碍。成功的研究将提供新颖的见解 进入该维修系统的脆弱性，可能有助于临床上的可行发展 改善肾脏疾病肾脏修复效率和效率的相关工具。