MicroRNAs and their applications in kidney diseases

Abstract

MicroRNAs (miRNAs) are short, non-coding RNAs that employ classic Watson-Crick base-pairing to identify their target genes, ultimately resulting in destabilization of their target mRNAs and/or inhibition of their translation. The role of miRNAs in a wide range of human diseases, including those afflicting the kidney, has been intensely investigated. However, there is still a vast dearth of knowledge regarding their specific mode of action and therapeutic effects in various kidney diseases. This review discusses the latest efforts to further our understanding of the basic biology of miRNAs, their impact on various kidney diseases and their potential as novel biomarkers and therapeutic agents. We initially provide an overview of miRNA biology and the canonical pathway implicated in their biogenesis. We then discuss commonly employed experimental strategies for miRNA research and highlight some of the newly described state-of-the-art technologies to identify miRNAs and their target genes. Finally, we carefully examine the emerging role of miRNAs in the pathogenesis of various kidney diseases.

Figure 1. Schematic of miRNA maturation mediated by DICER

The 70-80 nucleotide (nt) long double stranded, precursor-miRNA is cleaved by Dicer at the stem-loop sequence into a single stranded, 20-22 nt long mature miRNA. This mature miRNA is subsequently loaded into the RNA Induced Silencing Complex (RISC), where it exerts its gene regulatory activity. Highlighted in red is the 5–8 nt miRNA seed sequence, which is complementary to target mRNAs and is the responsible element for miRNA:mRNA interactions.

Figure 2. miRNA biogenesis and mode of action

Pri-miRNA are transcribed by RNA Polymerase II (Pol II), processed to include a 5'-7meG cap and a 3'-poly-A tail, and cleaved by the first member of the microprocessor complex, the RNAse III enzyme Drosha/DGCR8, into a 70-80 nt long pre-miRNA. This pre-miRNA is exported out of the nucleus via Exportin-5/RanGTP, cleaved by Dicer into a mature 20-22nt long miRNA and loaded into the RNA Induced Silencing Complex (RISC). RISC guides the single stranded mature, active miRNA to its target mRNAs and based on sequence complementarity to the mRNA target site and miRNA seed sequence may perform several gene regulatory functions, including ribosomal mediated translation inhibition or mRNA degradation/destabilization.