MicroRNAs as Biomarkers and Therapeutic Targets in Inflammation- and Ischemia-Reperfusion-Related Acute Renal Injury

Abstract

Acute kidney injury (AKI), caused mainly by ischemia-reperfusion, sepsis, or nephrotoxins (such as contrast medium), is identified by an abrupt decline in kidney function and is associated with high morbidity and mortality. Despite decades of efforts, the pathogenesis of AKI remains poorly understood, and effective therapies are lacking. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level to control cell differentiation, development, and homeostasis. Additionally, extracellular miRNAs might mediate cell-cell communication during various physiological and pathological processes. Recently, mounting evidence indicates that miRNAs play a role in the pathogenesis of AKI. Moreover, emerging research suggests that because of their remarkable stability in body fluids, microRNAs can potentially serve as novel diagnostic biomarkers of AKI. Of note, our previous finding that miR-494 is rapidly elevated in urine but not in serum provides insight into the ultimate role of urine miRNAs in AKI. Additionally, exosomal miRNAs derived from stem cells, known as the stem cell secretome, might be a potential innovative therapeutic strategy for AKI. This review aims to provide new data obtained in this field of research. It is hoped that new studies on this topic will not only generate new insights into the pathophysiology of urine miRNAs in AKI but also might lead to the precise management of this fatal disease.

Keywords: acute kidney injury; biomarker; microRNA.

Figure 1

The possible model of intracellular and extracellular miRNAs after acute kidney injury in renal tubular cells. To respond to the acute injury, miRNAs are first transcribed as primary miRNAs (Pri-miRNAs) in renal tubular cells. Next, pri-miRNAs further cleave to the pre-miRNAs by the Drosha/DGCR8 microprocessor complex and then exported into the cytoplasm. In the cytoplasm, pre-miRNAs are then unwound by Dicer to the formation of double-stranded miRNAs which complex with argonaute (AGO) proteins. The mature miRNA guide strand is stably loaded into the RNA-induced silencing complex (RISC) along with AGO2 protein and GW182 to form mature RISC (miRISC) complex, while the other strand is thought to be degraded. The mature miRNAs in the miRISC can base pair with its target mRNAs and lead to the repression of protein translation or mRNA degradation. If the miRISC does not combine with its target strands, miRNAs can then be selected and sorted into the microvesicles (MVs), intermediate vesicles (IVs), or multivesicular bodies (MVBs). Exosomes are then secreted after translocation of MVBs from the cytoplasm to the plasma membrane by exocytosis. miRNAs could also secrete with the collaboration of high-density lipoprotein (HDL), AGO2, or other RNA-binding protein (RBP). Red arrows indicate the possible transport pathways of serum miRNAs (also named “circulating microRNAs”). Black arrows indicate the possible transport pathways of urinary miRNAs. Although most of these in urine remains unknown, the growing emergent data suggested urinary miRNAs could be novel biomarkers for acute kidney injury (AKI). Once miRNAs enter to the downstream target renal tubular cells, and then, again, form miRISC to base pair with its target mRNAs leading to mRNA silencing. Of note, the injection of miRNA targeted therapy, or stem-cell-derived miRNAs might be an innovative therapeutic strategy for AKI. ORF: open reading frame.