MicroRNAs in injury and repair

Abstract

Organ damage and resulting pathologies often involve multiple deregulated pathways. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate a multitude of genes at the post-transcriptional level. Since their discovery over two decades ago, miRNAs have been established as key players in the molecular mechanisms of mammalian biology including the maintenance of normal homeostasis and the regulation of disease pathogenesis. In recent years, there has been substantial progress in innovative techniques to measure miRNAs along with advances in targeted delivery of agents modulating their expression. This has expanded the scope of miRNAs from being important mediators of cell signaling to becoming viable quantitative biomarkers and therapeutic targets. Currently, miRNA therapeutics are in clinical trials for multiple disease areas and vast numbers of patents have been filed for miRNAs involved in various pathological states. In this review, we summarize miRNAs involved in organ injury and repair, specifically with regard to organs that are the most susceptible to injury: the liver, heart and kidney. In addition, we review the current state of knowledge on miRNA biology, miRNA biomarkers and nucleotide-based therapeutics designed to target miRNAs to prevent organ injury and promote repair.

Keywords: Heart; Injury; Kidney; Liver; MicroRNAs; Repair.

Figure 1. MiRNA expression, processing and function are highly organized

MicroRNA biogenesis begins with transcription of genomic DNA by RNA polymerase II and can be mediated by many common transcription factors. Often, large RNA stem-loop structures called pri-miRNAs are formed directly. Drosha then cleaves pri-miRNAs to form intermediate stem-loop structures called pre-miRNAs. Alternatively, pre-miRNAs can form through an intermediate called a “miRtron” from splicing of mRNA. Exportin 5 (XPO5) then transports pre-miRNAs through nuclear pore complexes (NPC) into the cytosol. In the cytosol, Dicer cleaves pre-miRNAs to form microRNA duplexes. Argonaute 2 (AGO2) then mediates the dissociation of the miRNA duplex to form two mature miRNAs. These two miRNAs are deemed “5p” or “3p” depending on whether they originate from the 5′ or 3′ end of the pre-miRNA, respectively. Depending on the context or specific miRNA, mature miRNAs will either assemble within RNA-induced silencing complexes (RISC), degrade or may reenter the nucleus via Importin 8 (IPO8) to regulate transcription. After RISC assembly, miRNAs can bind to mRNAs with their complementary seed region to the 3′ untranslated region (UTR), 5′ UTR or the open reading frame (ORF). MiRNAs then regulate protein production either by promoting mRNA degradation or by inhibiting translation.

Figure 2. MiR-122 is a biomarker and therapeutic target in liver disease

MiR-122 is the most abundant miRNA in the liver and can increase or decrease in the liver tissue depending on the injury or disease. In diverse forms of liver injury and disease, miR-122 is secreted into the blood within small vesicles, dead cells or bound to RISC proteins or high-density lipoproteins. MiR-122 has been successfully utilized as a biomarker of various forms of liver injury and liver diseases such as HCV. Because of its involvement in HCV replication, miR-122 has also been successfully targeted pharmacologically with an inhibitor, Mirvirsen, which is currently in clinical trials.

Figure 3. Diverse approaches have been developed using miRNAs that can promote heart regeneration

Cardiomyocytes (CMs) may be the target of injury from drugs, environmental chemicals or from myocardial infarction (MI). Following injury, cardiomyocytes die and do not normally recover. Many different approaches have been developed with specific miRNAs or combinations of miRNAs that promote cardiac regeneration and recovery.

Figure 4. MiR-21 mediates kidney injury and causes the progression of fibrosis

Following diverse forms of kidney injury, miR-21 is upregulated in kidney cells including the tubular epithelium, glomerular cells, myofibroblasts and infiltrating macrophages. MiR-21 mediates kidney injury by decreasing lipid oxidation, deregulating metabolic processes and increasing reactive oxygen species (ROS). In addition, miR-21 is secreted in the urine within small vesicles, dead cells or bound to RISC proteins or high-density lipoproteins. MiR-21 can be measured in the sediment or supernatant of urine samples as a biomarker of kidney injury. Because of the role of miR-21 in promoting fibrosis, a miR-21 inhibitor, RG-012, is in clinical trials to treat Alport nephropathy.