Role of mitochondrial microRNAs (mitomiRs) in endogenous renal repair

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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.