Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression. They have important roles during kidney development, homeostasis and disease. In particular, miRNAs participate in the onset and progression of tubulointerstitial sclerosis and end-stage glomerular lesions that occur in various forms of chronic kidney disease (CKD). Therefore, miRNAs represent potential new therapeutic targets for a debilitating disease that continues to increase in prevalence worldwide and for which fully effective therapies are lacking. Several lines of research aimed at improving common CKD diagnostic tools and avoiding invasive kidney biopsies have also identified circulating miRNAs as possible diagnostic and even prognostic biomarkers of kidney disease. This Review discusses current understanding of the function of miRNAs in CKD, focusing on functions specifically involved in the transforming growth factor β1 pathway, which is activated in CKD. miRNAs that, according to available evidence, seem to be involved in diabetic nephropathy, IgA nephropathy, lupus nephritis, polycystic kidney disease and graft rejection, are also discussed.
Key points
- MicroRNAs (miRNAs) are key players in kidney development and physiology
- Transforming growth factor β1 is a major regulator of kidney fibrosis; its signalling is finely regulated by miRNAs
- miRNAs contribute to both the induction and progression of chronic kidney disease (CKD)
- Current translational research on miRNAs in kidney disease is mainly focused on developing reliable biomarkers for diagnosis and prognosis of CKD and renal transplantation
- miRNAs represent novel therapeutic targets for CKD, but delivery and safety issues must be taken into account before translation into clinical practice
Introduction
Chronic kidney disease (CKD) is an important public health problem that is closely linked to major non-communicable diseases such as diabetes mellitus and hypertension.1 Less common causes of CKD are hereditary diseases such as polycystic kidney disease (PKD), IgA nephropathy (IgAN) and lupus nephritis, or herbal and environmental toxins. Regardless of the disease aetiology, progression of CKD results in tubulointerstitial and glomerular fibrosis owing to excessive deposition of extracellular matrix (ECM). Other key features of CKD are inflammatory cell infiltration, tubular cell atrophy, mesangial cell hypertrophy and podocyte apoptosis.2 All of these pathological events are mainly instigated by the cytokine transforming growth factor β1 (TGF-β1).3
Current therapies that target the renin–angiotensin–aldosterone system4 are not always effective in halting progression to end-stage renal disease, a condition that requires renal replacement therapy by dialysis or kidney transplantation. Blockade of TGF-β1 signalling using TGF-β1 neutralizing antibodies or specific inhibitors of TGF-β1 receptors might be a promising therapeutic approach for CKD as these strategies have been shown to attenuate renal fibrosis in various animal models.5 The success of these approaches in preclinical studies has prompted the search for therapies that interfere with the epigenetic regulation of TGF-β and genes involved in the TGF-β signalling pathway. In this context, non-coding RNA species, including microRNAs (miRNAs), have been widely implicated in the pathogenesis and progression of CKD, particularly in the regulation of TGF-β1-mediated fibrosis. Correction of miRNA expression by in vivo delivery of miRNA mimics or inhibitors has therefore emerged as a promising novel therapeutic strategy for the treatment of CKD. In addition, several lines of current research aimed at improving common CKD diagnostic tools and avoiding invasive kidney biopsies have identified circulating miRNAs as possible diagnostic and even prognostic biomarkers.6, 7 This Review focuses on current research investigating the roles of miRNAs in normal kidney physiology and diseases; particular attention is given to the TGF-β1 pathway and its regulation by miRNAs.
Biogenesis and function of miRNAs
miRNAs are epigenetic regulators of gene expression that are able to modulate several cellular processes, from development to disease conditions. The human miRNAome is composed of 1,881 precursors and 2,588 mature miRNAs, which regulate at least 60% of protein-coding genes.8 Since 2010, the number of miRNAs included in miRBase has grown by approximately two-thirds owing to the advent of small RNA deep-sequencing techniques.9
Here, we briefly mention the key points of miRNA biogenesis and function, as these processes are described thoroughly elsewhere.10, 11 Transcription of miRNAs occurs from individual or clustered genes (that is, the miR-194–192 cluster), although some miRNAs can be encoded from distinct genomic loci.12 Genes encoding miRNAs are located in non-coding sequences or in introns of either protein-coding genes (miR-trons) or non-coding RNA.13 Intronic miRNAs are usually coordinately expressed with their host gene and most of the time they both affect the same signalling pathway.14, 15, 16
RNA polymerase II transcribes miRNAs in the nucleus as long capped and polyadenylated hairpin transcripts, called primary miRNAs (pri-miRNAs). These are processed into smaller ~70 nucleotide stem–looped structures, called precursor miRNAs (pre-miRNAs) by the ribonuclease III-like enzyme Drosha together with the microprocessor complex subunit DGCR8. Pre-miRNAs are then exported to the cytoplasm by exportin-5/GTP-binding nuclear protein Ran, where the ribonuclease Dicer yields 22 nucleotide miRNA duplexes consisting of the guide and passenger strands (miRNA:miRNA*). The guide strands are finally assembled into the RNA-induced silencing complex (RISC) and bind through their 'seed sequence' (nucleotides 2–8) to fully or partially complementary sites within the 3′ untranslated region of target mRNAs. miRNAs rarely bind to the coding regions of mRNA or genomic DNA, including promoter regions.17 Target recognition by miRNAs leads to mRNA translational repression and/or mRNA deadenylation and decay,18, 19 although positive regulation has been described in a few cases (Figure 1).20, 21 Beyond the simplistic concept that miRNAs act as repressors of a single transcript, emerging evidence indicates that they are modulators of many hundreds of proteins often involved in related signalling pathways.22, 23
Mature miRNAs possess distinct features that make them potentially suitable as therapeutic agents, including their short sequence and their high homology across multiple vertebrate species. Manipulation of the activity of specific miRNAs in the kidney can be achieved by in vivo delivery of mimics to restore miRNA levels or inhibitors to block miRNA function. miRNA mimics are double-stranded synthetic oligonucleotides that accomplish the endogenous functions of the miRNA of interest, but following chemical modifications possess increased stability and are efficiently taken up by cells. The most widely adopted strategy so far to block miRNA function is with chemically modified oligonucleotides (anti-miRs) designed against the mature miRNA sequence that are stable in circulation and are cell permeable (2′-O-methyl-group-modified oligonucleotides or locked nucleic acid anti-miRs). In addition to anti-miRs, miRNA inhibition can be achieved by expression of miRNA-target sequences able to capture pathogenic miRNAs (miRNA sponge), short hairpin RNA plasmids to abrogate miRNA expression via RNA interference, or using oligonucleotides complementary either to the 3′ untranslated region of the target mRNA binding site sequence (masking approach) or to the sequence of the miRNA (erasers).
Many studies in experimental animal models have focused on the therapeutic potential of miRNAs in CKD and promising results in halting renal fibrosis have been obtained by knocking down miR-21,22, 65, 92 miR-29c,99 miR-214,23 miR-433,94 and miR-19269, 76 or overexpressing miR-29b (Table 2).66, 80 Successful kidney transfection was achieved by intraperitoneal, intravenous or subcutaneous injection of either mimics or inhibitors or, more frequently, by intravenous injection of plasmids expressing miRNAs or short-hairpin RNAs.
However, many obstacles must be overcome before miRNA-based therapies for CKD can be translated into clinical practice, including delivery methods and safety concerns. Indeed, the target miRNA should be kidney-specific in order to avoid any potential adverse effects in other tissues and organs, and should affect only one target (or targets acting in the same pathway) to avoid effects on unintended templates, as in the case of miR-21, the knockdown of which induces cell death in addition to halting renal fibrosis.65 So far, these limitations have been partially overcome either by local administration of miRNA-based drugs or by using vectors containing kidney-specific and inducible promoters.
Conclusions
The importance of miRNAs in the kidney field is increasingly recognized as they enable researchers to understand in-depth the pathways that have a role in kidney physiology and disease. They can also provide an explanation for divergent transcriptomic and proteomic data. Moreover, an miRNA-based therapy that either restores or blocks miRNA expression and activity is very attractive, especially now that the first miRNA-targeted drug (miravirsen for the treatment of hepatitis C) has entered a phase II clinical trial.135 So far, the potential of miRNAs as an effective antifibrotic therapy has been demonstrated only in experimental models of CKD because many safety concerns must be resolved, from the delivery method to the adverse effects on alternative templates. Instead, a more impending application is the detection and quantification of circulating miRNAs as a novel non-invasive, repeatable method to identify and monitor the degree of disease. However, because most miRNAs are highly pleiotropic and act differently depending on the cell type, a single miRNA is unlikely to be able to diagnose and predict a form of CKD. Instead, a network of correlated miRNAs must be considered.
Nature Reviews Nephrology | Review
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