Role of mitochondrial microRNAs (mitomiRs) in endogenous renal repair

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干扰内源性肾脏修复机制，如CD 133 +/CD 24+分散的肾小管样 细胞（STC），可以增殖，其后代再分化为肾小管上皮细胞，以取代失去的 邻近受损的肾小管细胞。我们以前的研究表明，实验RAS损害了 通过诱导其线粒体的结构和功能异常来增强猪STC的修复能力。 然而，RAS诱导的STC线粒体损伤的基础过程仍不清楚。 微RNA（micro-RNAs，miRNAs）是一种非编码RNA片段，在转录后调节基因的转录， 基因表达miRNA基因在细胞核中转录，这导致产生初级和前初级RNA。 miRNA前体和随后成熟的miRNA。虽然大多数成熟的miRNAs存在于 在细胞质中，很少有称为“mitomiR”的miRNAs易位到细胞质中，以沉默相关基因的表达。 线粒体的功能。 我们的初步数据表明，RAS增加猪STC中mitomiRs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 和功能障碍。我们的初步实验还表明，mitomiRs的启动子和增强子表现出高表达， 5-胞嘧啶（5 hmC）的羟甲基化，这是一种表观遗传标记，是由10- 十一易位甲基胞嘧啶双加氧酶（泰特）。RAS中的肾缺血可能改变mitomiR 生物合成和干扰STC中的线粒体功能。这可能部分由表观遗传介导 在mitomiR调控区域内的5 hmC过程和/或增加mitomiR向线粒体的输入。 支持这一建议的工作假设是STC中mitomiR表达的改变是STC的基础。 RAS诱导STC线粒体损伤，钝化STC的旁分泌功能和能力， 保留狭窄后的肾脏将追求三个具体目标： RAS-STC中的mitomiR表达诱导STC中的线粒体结构损伤和功能障碍。目标二： 将测试RAS是否施加增加STC中mitomiR表达的表观遗传变化。目标3：意志测试 异常的mitomiR线粒体输入是否有助于STC功能障碍。成功的研究将提供 新的见解，这种修复系统的脆弱性，并可能有助于发展可行的 临床相关工具，用于改善肾脏疾病中肾脏修复的效用和功效。

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.