Modulation of polycystic kidney disease by non-coding RNAs
Introduction
The vast majority of the genome contains regions that do not code for proteins [1]. Historically termed as the ‘junk DNA,’ it is now known that a significant portion of this DNA undergoes transcription to give rise to non-coding RNAs (ncRNAs) with pivotal functions [1]. These RNAs, as the name suggests, do not encode for proteins but rather remain as RNAs during their lifetime and regulate gene/mRNA expression and mRNA metabolism.
ncRNAs are of two types - long ncRNAs (lncRNAs) that are >200 nucleotides in length and short ncRNAs of <30 nucleotides in length [2]. There are three major classes of short ncRNAs - miRNAs, siRNAs, and piRNAs [3]. Amongst the ncRNAs, miRNAs the most are widely studied. Compelling evidence supports the idea that miRNAs are novel regulators of disease pathogenesis [4,5]. First, aberrant miRNA expression/function is observed in numerous diseases such as cancer, tissue fibrosis, congenital and developmental conditions, and various monogenetic disorders including polycystic kidney disease (PKD). Second, gain and loss-of-function approaches causally link abnormal activity of many miRNAs to the progression of these diseases. Third, the pathogenic miRNAs contribute to the dysregulation of large gene networks in various diseases. Finally, these observations have led to the realization that miRNAs are novel drug targets for the treatment of many complex diseases. Indeed, multiple miRNA-based drugs have now advanced to human clinical trials for the treatment of cancer, tissue fibrosis, and two monogenic kidney diseases – Alport syndrome and autosomal dominant polycystic kidney disease (ADPKD).
PKD is amongst the most common human monogenic disease caused primarily by mutations in PKD1 or PKD2. The clinical hallmark of this disorder is the massive bilateral kidney enlargement due to innumerable cysts. The cysts are lined by hyperproliferative and hypersecretory cyst epithelial cells, which cause uncontrolled cyst growth and expansion, ultimately resulting in kidney failure. Several signaling pathways, including cAMP, mTOR, and cMyc have been known for a long time to drive PKD progression [6]. Recent work indicates that miRNA-mediated signaling is a key new driver of PKD pathogenesis [[7], [8], [9], [10]]. This review focuses on the progress made so far in our understanding of the role of miRNAs in PKD with an emphasis on the therapeutic targeting of these ncRNAs in PKD treatment.
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miRNA biogenesis and mechanism of action
miRNAs are ~22 nucleotides double-stranded RNA molecules and were first discovered in 1993 in C.elegans as regulators of larvae patterning [11,12]. Since this initial discovery, it has become clear that miRNAs are integral to virtually all aspects of mammalian biology ranging from the initial stages of embryo formation, stem cell biology and organ development to immune response, tissue injury/repair, aging, and disease progression [13,14].
miRNAs are produced either from intragenic (located
miRNAs in kidney development and homeostasis
The embryonic kidney consists of two precursor tissues: the metanephric mesenchyme and the ureteric bud [[21], [22], [23]]. Molecular signals from the ureteric bud induce the nephron progenitor cells of the metanephric mesenchyme to undergo differentiation into renal vesicles, which eventually give rise to glomeruli and nephrons [21,22]. Conversely, the metanephric mesenchyme induces branching morphogenesis of the ureteric bud, which differentiates into the collecting duct network [23]. During
miRNAs: new regulators of PKD pathogenesis
Numerous miRNAs are aberrantly expressed in murine and human forms of ADPKD. However, only a few have been causally linked to ADPKD progression. In the following sections, we discuss two cyst-promoting (miR-21 and miR-17) and cyst-suppressing (miR-193 and miR-214) miRNAs.
miR-21
miR-21 is an evolutionarily conserved and an extensively studied oncogenic miRNA [41]. The miR-21 gene is located within the protein-coding TMEM49 gene; however, it is transcribed independently via its own promoter [42] (Fig. 2). Multiple genomic regions in TMEM49 introns function as putative promoter regions of miR-21 [43,44]. miR-21 is broadly expressed in many cell types during development and, this includes the kidney epithelium and podocytes. Surprisingly, despite the widespread expression
miR-17–92 cluster
The miR-17–92 cluster was amongst the first miRNAs found to be amplified in cancerous tissues earning it the moniker ‘oncomir-1’ [65]. This finding sparked an intense interest in understanding its role in development and disease. miR-17–92 is a polycistronic miRNA cluster, which produces six individual miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a) [66,67]. The cluster is located within a 7 kb non-protein coding gene MIR17HG or C13orf25 (Fig. 2) and is evolutionarily
Cyst suppressing miRNAs
miR193-3p is a tumor suppressor miRNA [[83], [84], [85], [86]]. During ADPKD progression, its activity is suppressed [87]. Parallel microarray analysis for miRNA and mRNA expression on cell lines derived from normal kidneys and human ADPKD kidneys has shown that miR193b-3p is one of two significantly downregulated miRNAs. This miRNA functions by inhibiting several factors that regulate cell proliferation, such as Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4) [[88], [89], [90], [91]]. ErbB4 activity
Pharmacological modulation of miRNA activity
RNA-based drugs predate the discovery of miRNAs by a couple of decades. The RNA-based approach is applied in two ways: first, is the antisense oligonucleotide (ASO)-based approach [[93], [94], [95], [96]]. ASOs bind to target mRNAs and physically prevent ribosomes from translating the mRNA. In this way, the ASOs act as steric inhibitors of mRNA translation. ASOs can also be designed such that upon binding to target mRNAs, they recruit RNAase H, which degrades the mRNA [97]. The second approach
miRNA-based therapeutics for PKD
The first miRNA drug to be tested in humans was Mirvirasen, an LNA-modified anti-miR-122, for the treatment of Hepatitis C (HCV) [110]. In a phase 2A clinical trial, this drug demonstrated remarkable efficacy in suppressing HCV [111]. Although a follow-up clinical trial has not yet been performed, Miravirasen has provided the initial clinical proof of concept efficacy for the miRNA-based therapeutics platform. Several other miRNA-based drugs have now entered human clinical development for
Conclusion
ADPKD is the most common genetic cause of renal failure. Current treatment options are limited. miRNAs have emerged as promising drug targets in ADPKD. The biological effects of three epithelial miRNAs (miR-17–92, miR-21 and miR-193b-3p) and one stromal miRNA (miR-214) have been evaluated in ADPKD. miR-17–92 and miR-21 promote disease progression in ADPKD. Conversely, miR-193b-3p, and miR-214 attenuate cyst growth. These studies have led to the development of miRNA-based drugs for the treatment
Credit authors
Harini Ramalingam, Matanel Yheskel, and Vishal Patel wrote this review.
Declaration of Competing Interest
Vishal Patel has applied for a patent related to the treatment of polycystic kidney disease using miR-17 inhibitors. The Patel lab has a sponsored research agreement with Regulus Therapeutics. The remaining authors declare no conflict of interests.
Acknowledgements
The work from the authors laboratory is supported by National Institute of Health (R01DK102572) and the Department of Defense (D01 W81XWH1810673) to Vishal Patel. Harini Ramalingam is supported by the PKD Foundation Fellowship Grant.
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