Open Access This article is
- freely available
Int. J. Mol. Sci. 2019, 20(8), 1977; https://doi.org/10.3390/ijms20081977
Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis
EA 4483-IMPECS-IMPact of Environmental ChemicalS on Human Health, Univ. Lille, 59045 Lille CEDEX, France
Département de la Recherche en Santé, CHU Lille, 59037 Lille, France
Service de Néphrologie, CHU Lille, 59037 Lille, France
Service de Toxicologie et Génopathies, CHU Lille, 59037 Lille, France
Author to whom correspondence should be addressed.
Received: 28 March 2019 / Accepted: 20 April 2019 / Published: 23 April 2019
Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic options are available and the molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the role of non-coding RNAs, and in particular microRNAs (miRNAs), has been described in kidney fibrosis. Seminal studies have highlighted their potential importance as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review will summarize recent scientific advances and will discuss potential clinical applications as well as future research directions.
Keywords:non-coding RNAs; microRNAs; long non-coding RNAs; renal fibrosis; biomarkers; therapeutics targets
Chronic kidney disease (CKD) is increasingly recognized as a major public health concern. CKD prevalence has been estimated to be 8–16% worldwide . In particular, CKD has been evaluated to affect more than 10% of the western population . The common feature of CKD is renal fibrosis, which contributes to the progressive and irreversible decline in renal function and is associated with high morbidity and mortality.
Renal fibrosis, defined as an aberrant wound healing process in response to chronic injury, is characterized by the progressive and persistent accumulation of extracellular matrix components (ECM) in the kidney, ultimately leading to renal failure. As tissue scarring affects all compartments of the kidney, renal fibrosis is typically associated with glomerulosclerosis, arteriosclerosis and tubulointerstitial fibrosis . Disruption of the epithelium and/or endothelium integrity during injury results in the activation of a complex cascade of molecular and cellular events. First, an inflammatory response initiates the release of profibrotic cytokines, chemokines and growth factors, which in turn promotes the proliferative phase of the scarring process characterized in particular by the recruitment and activation of fibroblasts into ECM-secreting myofibroblasts [3,4]. Finally, ECM accumulation results in the formation of a permanent fibrotic scar associated with renal tissue remodeling . Once deposited, ECM components are further cross-linked and acquire resistance properties to degradation, precluding fibrosis resolution .
Although histological analysis of renal biopsies represents the gold standard to evaluate fibrosis, indirect biological parameters such as evolution of estimated Glomerular Filtration Rate are widely used in clinical practice for monitoring the progression of fibrotic lesions [7,8]. Furthermore, no specific treatment directly targeting fibrosis is currently approved . Therefore, identifying new therapeutic targets and innovative diagnostic and/or prognostic biomarkers remains critical.
Recently, among the various mechanisms triggering fibrogenesis, non-coding RNAs (ncRNAs) have emerged as important regulators of this deleterious process [9,10,11,12,13].
In this review, we summarize the implication of ncRNAs in renal fibrosis and their potential value as either biomarkers or therapeutic targets, with an emphasis on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs).
2. Non-Coding RNAs
New high-throughput technologies have revolutionized our understanding of the genome. Indeed, transcriptome of higher eukaryotic organism is far more complex than anticipated and contains large amounts of RNA molecules without coding potential (only 2% mRNAs in humans). Besides transfer and ribosomal RNAs that have been known since the 1950s, non-coding RNAs (ncRNAs) form a large and heterogenous class of RNA species involved in the regulation of gene expression. Non-coding RNAs are classified according to their length, localization and/or function into long non-coding RNAs (lncRNAs), microRNAs (miRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs) and PIWI-interacting RNAs (piRNAs) (Figure 1) [14,15,16,17]. Given that the role of some classes of ncRNAs (including siRNAs, snoRNAs or piRNAs) in kidney fibrosis remains largely unknown, this review will be restricted to miRNAs and lncRNAs.
2.1. microRNAs (miRNAs)
miRNAs are ncRNAs of about 22 nucleotides usually conserved between species and involved in post-transcriptional regulation of gene expression. Currently, about 2700 mature miRNAs have been identified in humans, regulating at least 60% of mRNAs (miRbase v.22.1, October 2018 ). As miRNAs are involved in a vast array of physiological processes, such as embryogenesis, cellular homeostasis and differentiation . Their aberrant expression plays a causative role in most complex disorders such as cancer, cardio-vascular diseases and fibro-proliferative disorders [20,21,22,23].
About 60% of miRNAs are localized in intergenic regions and possess their own transcriptional unit . Other miRNAs are localized in intron of coding genes and are either co-transcribed with their host genes or under the control of a specific promoter [25,26]. miRNAs are usually transcribed by RNA polymerase II into a primary transcript, termed pri-miRNA. This pri-miRNA is then processed into a pre-miRNA of about 70 nucleotides by a multiproteic complex, called microprocessor and composed of two subunits: The RNAse III endonuclease DROSHA and the RNA binding protein DGCR8 (DiGiorge Critical Region 8). The pre-miRNA is recognized by EXP5 (Exportin 5)-Ran-GTP and exported to the cytoplasm. The last step of maturation is catalyzed by the RNAse III DICER associated with TRBP (TAR RNA binding protein). The PAZ domain (PIWI-AGOZWILLE) of the complex allows the recognition and positioning of DICER, then the RNAse III domain cleaves the pre-miRNA loop, generating a 22-nucleotide miRNA duplex . The association with an Argonaute protein into the RISC (RNA-induced silencing complex) allows the dissociation of the duplex . The passenger strand (termed miRNA*) is then cleaved and released into the cytoplasm for degradation  whereas the guide strand, or mature miRNA, persists within RISC . When both strands lead to a mature miRNA, they are identified by the suffix -3p or -5p depending on whether they come from the 3′or 5′ end of their precursor.
By preferentially binding on specific sequences, called “seed” sequences, which are mainly localized in the mRNA 3’-UTR (UnTranslated Region), mature miRNAs induce the degradation of the target mRNAs if miRNA-mRNA complementarity is perfect. However, this mechanism is minor in animals. Indeed, in the majority of cases, miRNAs regulate the expression levels of their target mRNAs by the recruitment of protein partners responsible for the activation of de-adenylation and de-capping associated with the 5′-to-3′ decay of mRNAs and possibly to translational repression mechanisms .
2.2. Long Non-Coding RNAs (lncRNAs)
In the human genome, about 30,000 lncRNA transcripts have been identified to date (GENCODE v29, ). LncRNAs, which are defined by being larger than 200 nucleotides, share common features with mRNAs, including being transcribed by RNA polymerase II, capped, cleaved, spliced, and polyadenylated [32,33].
LncRNA members are a heterogeneous family that can be subdivided according to their biogenesis loci into intergenic lncRNAs (lincRNAs), intronic lncRNAs, antisense lncRNAs (aslncRNA or natural antisense transcripts, NATs), bidirectional lncRNAs, and enhancer RNAs (eRNAs) [34,35,36,37] (Figure 2). Their functions are still poorly explored due to their subcellular localization  and their tissue- and temporal-specific expression . Moreover, the low conservation of lncRNAs between species is a major obstacle to their identification and characterization in animal models . Nevertheless, lncRNAs have been shown to display wide-ranging functions, probably due to their ability to bind to either DNA, RNA or protein. In particular, seminal functional studies have demonstrated their important role in the modulation of gene expression or DNA remodeling in physiological and pathological processes .
3. miRNAs Implicated in Renal Fibrosis
Among the various classes of ncRNAs, miRNAs have first retained the attention of the scientific community. Many studies that focused on miRNAs in renal fibrosis have been published and allowed the identification of about thirty miRNAs with either an anti-fibrotic or pro-fibrotic effect, also called “fibromiRs” [4,40]. While Table 1 outlines publications highlighting the major role of miRNAs in renal fibrosis, we will describe more precisely the role of few particularly well-characterized miRNAs.
A large number of studies have emphasized the role of miR-21 in tissue fibrosis, notably in pulmonary , cardiac  or renal fibrosis . The miR-21 gene locus is located within the TMEM49 gene coding for Vacuole Membrane Protein 1 . Interestingly, while miR-21 is one of the most highly expressed miRNAs in the healthy kidney , studies suggest that loss of miR-21 has no effect on development or healthy tissue function. This could be explained by its sequestration into an intracellular compartment. Nevertheless, in various stress conditions, miR-21 could be released into the cytoplasm to exert its regulatory functions [42,113]. In different experimental models such as the renal fibrosis (unilateral ureteral obstruction (UUO) mouse model, acute kidney injury (ischemia-reperfusion model) or diabetic nephropathy (db/db mice, streptozotocine-induced diabetes)), miR-21 is highly expressed in injured kidney regions [41,42,53,57]. Overexpression of miR-21 was also confirmed in renal allograft biopsies, in renal tissues of patients with IgA nephropathy or with Alport Syndrome exhibiting severe fibrotic injuries, particularly in regions enriched in fibroblasts/myofibroblasts, in the tubular epithelium and glomeruli [58,59,60]. The deleterious role of miR-21 in renal fibrosis was further explored using miR-21 null mice. Following UUO or ischemia-reperfusion injuries, miR-21-/- mice exhibited less fibrosis. Moreover, authors showed that miR-21 is also involved in lipid metabolism and mitochondrial redox regulation . While only a limited number of miR-21 target genes have been experimentally validated, miR-21 has been demonstrated to be involved in the regulation of critical signaling pathways related to fibrogenesis such as cellular proliferation (PTEN) , apoptosis (PDCD4, Bcl2) [43,62,63], regulation of cellular metabolism (PPARα, PHD2) [44,45,46], inflammation (MKK3) [47,48], ECM components (Reck, TIMP3) [49,50,51,52], TGF-β signaling pathway (Smad7) , angiogenesis (Reck, THSP-1, PHD2) [46,49,50,55] and autophagy (Rab11a) .
miR-214 has been shown to act as a fibromiR in several types of tissue fibrosis, including liver  and heart fibrosis . miR-214 has been also consistently associated with renal fibrosis. It is in particular upregulated by the activation of the transcription factor TWIST in response to hypoxia in renal tubular epithelial cells . Moreover, Denby et al., using miR-214 null mice and the UUO model of kidney fibrosis, showed that miR-214 promotes renal fibrosis independently of TGF-β pathway . Similarly, treatment with an antagonist of miR-214 before UUO protected against fibrogenesis without blocking Smad2/Smad3 activation and TGF-β signaling . Other studies have mechanistically linked miR-214 pro-fibrotic function with the targeting of DKK3 (Wnt/β -catenin pathway) , CDH1 (EMT)  or PTEN (proliferation) .
3.3. miR-200 Family
Members of the miR-200 family include five members organized into two clusters, miR-200b/a/429 and miR-200c/141 [117,118]. In animal models of renal fibrosis either induced by UUO or gavage with adenine, miR-200 family members are consistently downregulated [98,99]. Indeed, the anti-fibrotic role of these miRNAs is mainly associated with epithelial differentiation  by protecting renal tubular cells from EMT process through the direct regulation of ZEB1/2 (zinc finger E-box-Binding homeobox proteins 1/2) and Ets-1 transcription factors [81,101,102,103]. Of note, miR-200 family is also involved in TGF-β signaling pathway by modulating TGF-β2 .
3.4. miR-29 Family
miR-29 family is composed of three members: miR-29a, miR-29b and miR-29c . Expression of miR-29abc is invariably downregulated during fibrosis and their low expression is associated with the up-regulation of ECM-related genes . In fact, decreased expression of miR-29 family members is a general downstream molecular event of TGF-β signaling, which is essential for the release of ECM components by fibroblasts, as miR-29 family members directly target multiple collagen isoforms and other ECM components [81,82,83].
In various animal models of renal fibrosis, expression of miR-29 members is downregulated regardless of the cause of injury [84,85]. Interestingly, TGF-β inhibited miR-29 expression not only in renal fibroblasts, but also in mesangial cells, epithelial cells and podocytes , suggesting that miR-29abc exert also an anti-fibrotic function in non-fibroblastic renal cells. For example, both Adam12 and Adam19 represent two pro-fibrotic targets of miR-29abc in renal tubular epithelial cells . Similarly, Hu et al. showed that miR-29 targets, in renal tubular epithelial cells, PIK3R2, an effector of PI3K/AKT signaling pathway involved in EMT induced by Angiotensin II . Nevertheless, the precise contribution of miR-29abc during fibrosis in non-stromal cells remains to be clarified, especially as Long et al. reported an increased expression of miR-29c in both podocytes and endothelial cells in a mouse model of diabetic nephropathy .
Data regarding the role of miR-192 in renal fibrosis are currently controversial. In fact, miR-192 is upregulated in various mouse models of CKD such as diabetic nephropathy, UUO and IgA nephropathy [105,106,107,108]. In line with this, treatment with an antagonist of miR-192 protected against fibrosis through induction of Zeb1/2 in diabetic nephropathy mouse model . By contrast, other studies have reported in vitro in renal cells exposed to TGF-β, in a mouse model of diabetic nephropathy as well as in renal tissue from patients exhibiting severe renal fibrotic lesions a downregulation of miR-192 [108,109]. Overall, data highlighting the versatile role of miR-192 in renal fibrosis represent a relevant example of the complexity of miRNA regulation mechanisms.
4. Long Non-Coding RNAs Implicated in Renal Fibrosis
Even if elucidation of the role of lncRNAs is still ongoing, it is now accepted that besides their involvement in physiological processes such as organ development, immunity or homeostasis, their modulation can occur in chronic multifactorial diseases .
In the context of fibrosis, few examples showing their pro-fibrotic role have been documented, such as MALAT1 in cardiac fibrosis, H19 and DNM3os in lung fibrosis, and MALAT1, lnc-LFAR1 and HIF1A-AS1 in liver fibrosis [120,121,122,123,124,125]. Although studies about lncRNAs and renal fibrosis are quite recent, their number has significantly increased in recent years. In particular, emerging data show that various lncRNAs are involved in renal fibrosis by playing a pro- or anti-fibrotic role (Table 2). Although many studies have shown a deregulation of lncRNA expression, we chose to only focus on mechanistic studies.
LncRNA Errb4-IR (np_5318), located in the ERBB4 intron region between the first and second exons, has been associated with renal fibrosis [134,135]. In the UUO mouse model, Errb4-IR was upregulated and strongly expressed in interstitial fibroblasts and injured tubular epithelial cells. Errb4-IR upregulation was also associated with fibrotic marker expression such as α-SMA or Collagen I. Moreover, in vivo silencing of Errb4-IR in the UUO mouse model significantly decreased fibrotic injuries . Feng et al. also assessed the mechanisms underlying the fibrogenic role of Errb4-IR and showed that, in addition to being induced by TGF-β/Smad3 signaling, Errb4-IR directly targets Smad7, which exerts anti-fibrotic functions . The pathological role of Errb4-IR in renal fibrosis was further confirmed in the context of diabetic nephropathy  by demonstrating that Errb4-IR also targets miR-29b, a well-established anti-fibrotic miRNA.
HOTAIR (HOX transcript antisense intergenic RNA), embedded in the HOXC locus, is known to drive cancerogenesis . Recently, two studies have demonstrated that HOTAIR is upregulated in renal fibrosis. In the UUO rat model, HOTAIR overexpression was associated with an upregulation of fibrotic and EMT markers as well as with a downregulation of miR-124, a miRNA involved in EMT and acting as a negative regulator of Nocth1 signaling pathway [130,131]. Moreover, lentiviral-mediated overexpression of HOTAIR in UUO rats, led to more severe injuries, such as inflammation, necrosis and collagen deposits, an elevated score of renal fibrosis and an overexpression of fibrotic markers compared to UUO alone. Mechanistically, it has been shown that HOTAIR activates the Notch1/Jagged1 signaling pathway by acting as a ceRNA (competing endogenous RNA—an lncRNA–miRNA duplex which prevents binding miRNA to its target and thus the target inhibition) with miR-124, which targets Notch1 and JAG1, and thereby promotes renal fibrosis [157,158].
In diabetic nephropathy, lincRNA Gm4419 was found to be involved in renal fibrosis. More precisely, in mesangial cells in high glucose conditions, overexpression of GM4419 was associated with fibrosis, inflammation and cell proliferation. Authors demonstrated that the NF-κB signaling pathway, which plays an important role in fibrogenesis and inflammation , was activated by GM4419 by interacting with its subunit p50. Moreover, p50 and GM4419 could have a synergistic effect in the inflammatory pathway .
5. New Therapeutic Targets and Innovative Biomarkers
5.1. New Therapeutic Targets
To date, the lack of specific anti-fibrotic therapies remains a critical need in clinical practice. As ncRNAs are involved in many critical pathogenic processes driving renal fibrosis, they represent attractive therapeutic targets. Currently, two strategies can be applied to manipulate ncRNA expression levels: The first relies on restoring the expression of a ncRNA when its level is decreased, the second is related to inhibiting the function of a ncRNA when its expression is increased.
5.1.1. miRNAs as Therapeutic Targets
To restore miRNA function, miRNA mimics or pre-miRNA have been developed. A modified synthetic RNA is introduced into cells as a duplex consisting of one strand identical to the mature miRNA of interest (guide strand) and the second antisense strand with a lower stability . In addition, chemical modifications such as 2′-Fluoro bases have been developed to increase the stability of the guide strand without interfering with the RISC complex . Other modifications include the use of 5′-O-methyl bases on the second strand to limit its incorporation into RISC complex . Finally, addition of cholesterol-like molecules improves the duplex cellular internalization . Although the use of such tools is widely developed for in vitro models, their application in vivo is hampered by delivery . Other approaches involved gene therapy techniques, using notably AAV-mediated miRNA delivery (adeno-associated virus). Indeed, AAVs allow the restoration of the physiological expression level of miRNA with low toxicity and without integration into the genome in a specific tissue or cellular type [159,162].
Such strategies have been successfully applied in preclinical mouse models of tissue fibrosis, including bleomycin-induced lung fibrosis, but still need to be evaluated in the context of kidney fibrosis . The renal tissue is indeed accessible to AAV gene delivery by different routes, including injection through the renal artery, injection into the parenchyma and retrograde injection via the ureter.
Concerning miRNA inhibition, several strategies have been developed, especially antisense oligonucleotides (termed antimiRs) which are widely used in preclinical models of tissue fibrosis and have also entered clinical trials . These molecules are also chemically modified in order to improve their affinity, pharmacokinetics, stability and cellular entrance. The major modifications include the addition on the ribose of particular groups such as 2′O-Methyl, 2′O-Methoxyethyl or 2′-Fluoro and also inclusion of bicyclic structures which lock the ribose into its preferred 3′ endo conformation and increase base-pairing affinity such as methylene bridging group, also known as LNA (locked nucleic acid). Such ribose modifications allow a reduction in the size of antimiRs without loss of affinity and specificity. Finally, backbone modifications such as phosphorothioate linkages or the addition of morpholino structures enhance nuclease resistance .
Finally, target site blockers (TSB) inhibit miRNA function by specifically preventing interaction between a miRNA and its target [166,167]. One advantage of this strategy relies on its specificity, as it does not affect expression of the other target genes, and thus reduces the risk of side effects.
In the context of renal fibrosis, proof-of-concept for miRNA targeting has been demonstrated for several fibromiRs. In particular, results indicated that miR-214 antagonism was associated with less fibrotic lesions in the UUO mouse model . In addition, an miR-21 antagonism injection prevented fibrotic injuries in UUO , diabetic nephropathy  or Alport  mouse models. Moreover, Regulus Therapeutics has developed a phase II clinical trial with a miR-21 antagonist in patients with Alport syndrome (RG-012; Regulus Therapeutics Inc.; clinical trial: NCT02855268). This drug candidate has currently received the orphan drug status from the FDA and the European Commission for the treatment of this rare disease.
5.1.2. lncRNAs as Therapeutic Targets
LncRNA deregulation is also viewed as an important driver of renal fibrosis, suggesting their potential value as therapeutic targets. Given their extensive secondary structures and their localization in nuclear and/or cytoplasmic compartments [15,34], pharmacological modulation of lncRNAs is more complex and, until recently, the options for targeting lncRNAs were limited. Moreover, the low conservation of lncRNAs between species is a major obstacle for preclinical validation [39,170]. However, recently, conceptual and technological advances in antisense oligonucleotide therapy offer new pharmacological options to modulate the expression or the function of lncRNAs. For example, the development of technologies including GapmeR-mediated lncRNA silencing, CRISPR inhibition or aptamers directed against lncRNA secondary structure represent novel opportunities to improve lncRNA knowledge and clinical translation .
In the context of renal fibrosis, lncRNA modulation remains an almost unexplored area. However, Kato et al. have used GapmeRs, an antisense oligonucleotide technology that induces target degradation in the nuclear compartment by recruiting RNAse H , in a mouse model of diabetic nephropathy. Interestingly, injection of such GapmeRs against lnc-MGG induced a decreased expression of profibrotic genes (TGF-β1, Col1a2, Col4a1, Ctgf) and prevented glomerular fibrosis, podocyte death and hypertrophy in diabetic mice . Otherwise, few studies have investigated the opportunity to downregulate lncRNA expression using short hairpin RNAs (shRNAs) by delivery of plasmids or through viral or bacterial vectors in vivo . Indeed, targeting of Errb4-IR was shown to improve renal fibrosis in the db/db mouse model . Moreover, in a UUO mouse model, Arid2-IR was also successfully inhibited by a shRNA .
Histological examination of biopsied tissue is considered the reference method for the diagnosis and staging of kidney fibrosis . However, as percutaneous tissue sampling of either native kidney or allograft remains associated with patient discomfort, risk for complications, histopathological interpretation variability and high cost , the development of alternative non-invasive diagnostic or prognostic biomarkers is an important clinical issue . Interestingly, ncRNAs that have been extensively reported to be dysregulated in fibrotic tissues, have also been detected in a large panel of human biological fluids including serum, plasma and urine [177,178,179].
In order to discover relevant biomarkers, miRNA profiling in several biofluids has been performed. Urine is a particularly interesting matrix to explore kidney function, even if miRNAs in urine are less abundant than in plasma or serum, since RNase activity has been reported to be quite high in urine . Cardenas-Gonzalez et al. have screened more than 2000 urinary miRNAs from patients with CKD. In particular, this study demonstrated that downregulation of miR-2861, miR-1915-3p and miR-4532 was associated with a poorer renal function, interstitial fibrosis and tubular atrophy in diabetic nephropathy . Another study profiled more than 1800 miRNAs in urine samples from patients with acute kidney injury. Among the 378 detected miRNAs, 19 were upregulated in patients with acute kidney injury, including miR-21, miR-200c and miR-423 . Sonoda et al. showed that miR-9a, miR-141, miR-200a, miR-200c and miR-429 from exosomes in rat urine were upregulated following ischemia-reperfusion injury . Moreover, Khurana et al. identified nine upregulated miRNAs (let-7c-5p, miR-222–3p, miR-27a-3p, miR-27b-3p, miR-296-5p, miR-31-5p, miR-3687, miR-6769b-5p and miR-877-3p) and seven downregulated miRNAs (miR-133a, miR-133b, miR-15a-5p, miR-181a-5p, miR-34a-5p, miR-181c-5p and miR1-2) in urine exosomes from patients with CKD compared to healthy controls . Finally, other studies showed that dysregulation of urinary miR-29c, miR-21 and miR-200b was correlated with renal fibrotic injuries in patients with CKD or in renal transplanted patients [185,186,187]. Altogether, these data indicate that detection of miRNAs in the urine could reflect the degree of the renal aggression .
Finally, miRNAs were also detectable in serum and, more specifically, in renal transplanted patients serum level expression of miR-21 was found to be associated with the severity of renal fibrosis injuries [58,189,190]. While promising, the clinical use of circulating miRNAs as biomarkers remains tempered by quality control and normalization issues. For example, hemolysis needs to be perfectly avoided since miRNAs can be released from blood cells, thus affecting the amount of detected circulating miRNAs . Furthermore, no standard endogenous control to normalize circulating miRNA levels has been clearly established and this concern is still debated [192,193]. The development of new technologies such as digital PCR (dPCR) are particularly interesting as this approach allows an absolute quantification without internal normalization [194,195].
Although the expression of many lncRNAs has been evaluated in the context of fibrosis, their validation as biomarkers is at an earlier stage than miRNAs. Nevertheless, identifying novel lncRNAs as biomarkers is of great interest, since lncRNAs are highly stable in biofluids, especially when they are included in exosomes or in apoptotic bodies  and could be present in extracellular vesicles . In renal fibrosis, Sun et al. compared the lncRNA profile in renal tissues and urines of UUO rats. Seven lncRNAs (five upregulated and two downregulated) were similarly modulated in renal tissues and urine. In addition, several conserved Smad3 binding motifs were identified in the sequence of the five upregulated lncRNAs . Altogether, these results raise the possibility of using urinary lncRNAs as non-invasive biomarkers of renal fibrosis. Otherwise, Gao et al. found that in the serum of patients with diabetic nephropathy, the upregulation of lncRNA NR_033515 was correlated with NGAL and KIM1 serum levels, and the severity of the disease . While both of these studies highlighted the potential of lncRNAs as non-invasive biomarkers for renal fibrosis, further studies are clearly required for the robust identification and validation of diagnostic and prognostic biomarkers.
7. Future Directions
NcRNAs, including the well-known miRNAs and the emerging lncRNAs, have been described to be implicated in a large number of physiological and pathological processes (Figure 3). In particular, their modulation between normal and fibrotic renal tissues not only strongly suggests that ncRNAs are involved in the development and the progression of kidney fibrosis, but also that ncRNAs may represent promising biomarkers. However, in contrast to miRNAs, the underlying mechanisms of most of the identified lncRNAs are yet to be determined. Considering both technological advances and rising scientific enthusiasm in lncRNA biology, we foresee that major discoveries will soon be achieved regarding the role of lncRNAs in kidney fibrosis.
The proof of concept of ncRNA expression modulation to treat fibroproliferative disorders has been elegantly demonstrated. Clinical translation of these potential new therapeutic targets should be considered a research priority and will undoubtedly represent a gold mine of new therapeutic targets that may lead to the development of novel anti-fibrotics.
Original draft preparation, C.V.d.H.; writing, C.V.d.H. and C.C.; review and editing, C.V.d.H., C.C., N.P. and F.G.
The APC was funded by Santélys association.
Conflicts of Interest
The authors declare no conflict of interest.
|ceRNA||Competing endogenous RNA|
|CKD||Chronic kidney disease|
|FDA||Food and Drug Administration|
|HOTAIR||HOX transcript antisense intergenic RNA|
|lncRNA||Long non-coding RNA|
|RISC||RNA-induced silencing complex|
|RPTEC||Renal proximal tubular epithelial cell|
|shRNA||Short hairpin RNA|
|UUO||Ureteral unilateral obstruction|
- Jha, V.; Garcia-Garcia, G.; Iseki, K.; Li, Z.; Naicker, S.; Plattner, B.; Saran, R.; Wang, A.Y.-M.; Yang, C.-W. Chronic kidney disease: Global dimension and perspectives. Lancet 2013, 382, 260–272. [Google Scholar] [CrossRef]
- Klinkhammer, B.M.; Goldschmeding, R.; Floege, J.; Boor, P. Treatment of renal fibrosis—turning challenges into opportunities. Adv. Chronic Kidney Dis. 2017, 24, 117–129. [Google Scholar] [CrossRef]
- Friedman, S.L.; Sheppard, D.; Duffield, J.S.; Violette, S. Therapy for fibrotic diseases: Nearing the starting line. Sci. Transl. Med. 2013, 5, 167sr1. [Google Scholar] [CrossRef]
- Pottier, N.; Cauffiez, C.; Perrais, M.; Barbry, P.; Mari, B. FibromiRs: Translating molecular discoveries into new anti-fibrotic drugs. Trends Pharmacol. Sci. 2014, 35, 119–126. [Google Scholar] [CrossRef] [PubMed]
- Gurtner, G.C.; Werner, S.; Barrandon, Y.; Longaker, M.T. Wound repair and regeneration. Nature 2008, 453, 314–321. [Google Scholar] [CrossRef]
- Lu, P.; Takai, K.; Weaver, V.M.; Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 2011, 3, a005058. [Google Scholar] [CrossRef]
- Levey, A.S.; Bosch, J.P.; Lewis, J.B.; Greene, T.; Rogers, N.; Roth, D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann. Intern. Med. 1999, 130, 461–470. [Google Scholar] [CrossRef] [PubMed]
- Berchtold, L.; Friedli, I.; Vallée, J.-P.; Moll, S.; Martin, P.-Y.; de Seigneux, S. Diagnosis and assessment of renal fibrosis: The state of the art. Swiss Med. Wkly. 2017, 147, w14442. [Google Scholar]
- Chung, A.C.-K.; Lan, H.Y. MicroRNAs in renal fibrosis. Front. Physiol. 2015, 6, 50. [Google Scholar] [CrossRef] [PubMed]
- Van der Hauwaert, C.; Savary, G.; Hennino, M.-F.; Pottier, N.; Glowacki, F.; Cauffiez, C. Implication des microARN dans la fibrose rénale. Nephrol. Ther. 2015, 11, 474–482. [Google Scholar] [CrossRef] [PubMed]
- Gomez, I.G.; Nakagawa, N.; Duffield, J.S. MicroRNAs as novel therapeutic targets to treat kidney injury and fibrosis. Am. J. Physiol. Renal Physiol. 2016, 310, F931–F944. [Google Scholar] [CrossRef][Green Version]
- Moghaddas Sani, H.; Hejazian, M.; Hosseinian Khatibi, S.M.; Ardalan, M.; Zununi Vahed, S. Long non-coding RNAs: An essential emerging field in kidney pathogenesis. Biomed. Pharmacother. 2018, 99, 755–765. [Google Scholar] [CrossRef]
- Jiang, X.; Zhang, F. Long noncoding RNA: A new contributor and potential therapeutic target in fibrosis. Epigenomics 2017, 9, 1233–1241. [Google Scholar] [CrossRef]
- Cech, T.R.; Steitz, J.A. The noncoding RNA revolution—Trashing old rules to forge new ones. Cell 2014, 157, 77–94. [Google Scholar] [CrossRef]
- Esteller, M. Non-coding RNAs in human disease. Nat. Rev. Genet. 2011, 12, 861–874. [Google Scholar] [CrossRef]
- Ulitsky, I.; Bartel, D.P. lincRNAs: Genomics, evolution, and mechanisms. Cell 2013, 154, 26–46. [Google Scholar] [CrossRef]
- Shi, X.; Sun, M.; Liu, H.; Yao, Y.; Song, Y. Long non-coding RNAs: A new frontier in the study of human diseases. Cancer Lett. 2013, 339, 159–166. [Google Scholar] [CrossRef] [PubMed]
- Kozomara, A.; Birgaoanu, M.; Griffiths-Jones, S. miRBase: From microRNA sequences to function. Nucleic Acids Res. 2019, 47, D155–D162. [Google Scholar] [CrossRef]
- Bartel, D.P. MicroRNAs: Target recognition and regulatory functions. Cell 2009, 136, 215–233. [Google Scholar] [CrossRef] [PubMed]
- Croce, C.M.; Calin, G.A. miRNAs, Cancer, and stem cell division. Cell 2005, 122, 6–7. [Google Scholar] [CrossRef]
- Small, E.M.; Olson, E.N. Pervasive roles of microRNAs in cardiovascular biology. Nature 2011, 469, 336–342. [Google Scholar] [CrossRef][Green Version]
- Li, G.; Zhou, R.; Zhang, Q.; Jiang, B.; Wu, Q.; Wang, C. Fibroproliferative effect of microRNA-21 in hypertrophic scar derived fibroblasts. Exp. Cell Res. 2016, 345, 93–99. [Google Scholar] [CrossRef] [PubMed]
- Bowen, T.; Jenkins, R.H.; Fraser, D.J. MicroRNAs, transforming growth factor beta-1, and tissue fibrosis. J. Pathol. 2013, 229, 274–285. [Google Scholar] [CrossRef]
- Corcoran, D.L.; Pandit, K.V.; Gordon, B.; Bhattacharjee, A.; Kaminski, N.; Benos, P.V. Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data. PLoS ONE 2009, 4, e5279. [Google Scholar] [CrossRef]
- Baskerville, S.; Bartel, D.P. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005, 11, 241–247. [Google Scholar] [CrossRef]
- Ozsolak, F.; Poling, L.L.; Wang, Z.; Liu, H.; Liu, X.S.; Roeder, R.G.; Zhang, X.; Song, J.S.; Fisher, D.E. Chromatin structure analyses identify miRNA promoters. Genes Dev. 2008, 22, 3172–3183. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Park, J.-E.; Heo, I.; Tian, Y.; Simanshu, D.K.; Chang, H.; Jee, D.; Patel, D.J.; Kim, V.N. Dicer recognizes the 5′ end of RNA for efficient and accurate processing. Nature 2011, 475, 201–205. [Google Scholar] [CrossRef][Green Version]
- Su, H.; Trombly, M.I.; Chen, J.; Wang, X. Essential and overlapping functions for mammalian Argonautes in microRNA silencing. Genes Dev. 2009, 23, 304–317. [Google Scholar] [CrossRef][Green Version]
- Liu, X.; Jin, D.-Y.; McManus, M.T.; Mourelatos, Z. Precursor microRNA-programmed silencing complex assembly pathways in mammals. Mol. Cell 2012, 46, 507–517. [Google Scholar] [CrossRef]
- Jonas, S.; Izaurralde, E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat. Rev. Genet. 2015, 16, 421–433. [Google Scholar] [CrossRef] [PubMed]
- Frankish, A.; Diekhans, M.; Ferreira, A.-M.; Johnson, R.; Jungreis, I.; Loveland, J.; Mudge, J.M.; Sisu, C.; Wright, J.; Armstrong, J.; et al. GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res. 2019, 47, D766–D773. [Google Scholar] [CrossRef]
- Quinn, J.J.; Chang, H.Y. Unique features of long non-coding RNA biogenesis and function. Nat. Rev. Genet. 2016, 17, 47–62. [Google Scholar] [CrossRef]
- Bunch, H. Gene regulation of mammalian long non-coding RNA. Mol. Genet. Genomics 2018, 293, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Chen, L.-L. Linking long noncoding RNA localization and function. Trends Biochem. Sci. 2016, 41, 761–772. [Google Scholar] [CrossRef]
- Kung, J.T.Y.; Colognori, D.; Lee, J.T. Long noncoding RNAs: Past, present, and future. Genetics 2013, 193, 651–669. [Google Scholar] [CrossRef]
- Derrien, T.; Johnson, R.; Bussotti, G.; Tanzer, A.; Djebali, S.; Tilgner, H.; Guernec, G.; Martin, D.; Merkel, A.; Knowles, D.G.; et al. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res. 2012, 22, 1775–1789. [Google Scholar] [CrossRef]
- Devaux, Y.; Zangrando, J.; Schroen, B.; Creemers, E.E.; Pedrazzini, T.; Chang, C.-P.; Dorn, G.W.; Thum, T.; Heymans, S.; Cardiolinc Network. Long noncoding RNAs in cardiac development and ageing. Nat. Rev. Cardiol. 2015, 12, 415–425. [Google Scholar]
- Ward, M.; McEwan, C.; Mills, J.D.; Janitz, M. Conservation and tissue-specific transcription patterns of long noncoding RNAs. J. Hum. Transcript. 2015, 1, 2–9. [Google Scholar] [CrossRef][Green Version]
- Ulitsky, I. Evolution to the rescue: Using comparative genomics to understand long non-coding RNAs. Nat. Rev. Genet. 2016, 17, 601–614. [Google Scholar] [CrossRef] [PubMed]
- Lv, W.; Fan, F.; Wang, Y.; Gonzalez-Fernandez, E.; Wang, C.; Yang, L.; Booz, G.W.; Roman, R.J. Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. Physiol. Genomics 2018, 50, 20–34. [Google Scholar] [CrossRef] [PubMed]
- Zarjou, A.; Yang, S.; Abraham, E.; Agarwal, A.; Liu, G. Identification of a microRNA signature in renal fibrosis: Role of miR-21. Am. J. Physiol. Renal Physiol. 2011, 301, F793–F801. [Google Scholar] [CrossRef]
- Chau, B.N.; Xin, C.; Hartner, J.; Ren, S.; Castano, A.P.; Linn, G.; Li, J.; Tran, P.T.; Kaimal, V.; Huang, X.; et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci. Transl. Med. 2012, 4, ra18–ra121. [Google Scholar] [CrossRef]
- Dong, J.; Zhao, Y.-P.; Zhou, L.; Zhang, T.-P.; Chen, G. Bcl-2 upregulation induced by miR-21 Via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells. Arch. Med. Res. 2011, 42, 8–14. [Google Scholar] [CrossRef]
- Zhou, J.; Wang, K.-C.; Wu, W.; Subramaniam, S.; Shyy, J.Y.-J.; Chiu, J.-J.; Li, J.Y.-S.; Chien, S. MicroRNA-21 targets peroxisome proliferators-activated receptor- in an autoregulatory loop to modulate flow-induced endothelial inflammation. Proc. Natl. Acad. Sci. USA 2011, 108, 10355–10360. [Google Scholar] [CrossRef]
- Zhang, K.; Han, L.; Chen, L.; Shi, Z.; Yang, M.; Ren, Y.; Chen, L.; Zhang, J.; Pu, P.; Kang, C. Blockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas. Cancer Lett. 2014, 342, 139–149. [Google Scholar] [CrossRef]
- Jiao, X.; Xu, X.; Fang, Y.; Zhang, H.; Liang, M.; Teng, J.; Ding, X. miR-21 Contributes to renal protection by targeting prolyl hydroxylase domain protein 2 in delayed ischaemic preconditioning. Nephrology 2017, 22, 366–373. [Google Scholar] [CrossRef]
- Xu, G.; Zhang, Y.; Wei, J.; Jia, W.; Ge, Z.; Zhang, Z.; Liu, X. MicroRNA-21 promotes hepatocellular carcinoma HepG2 cell proliferation through repression of mitogen-activated protein kinase-kinase 3. BMC Cancer 2013, 13, 469. [Google Scholar] [CrossRef]
- Li, Z.; Deng, X.; Kang, Z.; Wang, Y.; Xia, T.; Ding, N.; Yin, Y. Elevation of miR-21, through targeting MKK3, may be involved in ischemia pretreatment protection from ischemia–reperfusion induced kidney injury. J. Nephrol. 2016, 29, 27–36. [Google Scholar] [CrossRef]
- Zhou, L.; Yang, Z.-X.; Song, W.-J.; Li, Q.-J.; Yang, F.; Wang, D.-S.; Zhang, N.; Dou, K.-F. MicroRNA-21 regulates the migration and invasion of a stem-like population in hepatocellular carcinoma. Int. J. Oncol. 2013, 43, 661–669. [Google Scholar] [CrossRef][Green Version]
- Zhang, Z.; Li, Z.; Gao, C.; Chen, P.; Chen, J.; Liu, W.; Xiao, S.; Lu, H. miR-21 Plays a pivotal role in gastric cancer pathogenesis and progression. Lab. Investig. 2008, 88, 1358–1366. [Google Scholar] [CrossRef]
- Wang, N.; Zhang, C.; He, J.; Duan, X.; Wang, Y.; Ji, X.; Zang, W.; Li, M.; Ma, Y.; Wang, T.; et al. miR-21 Down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Dig. Dis. Sci. 2013, 58, 1863–1870. [Google Scholar] [CrossRef]
- Hu, J.; Ni, S.; Cao, Y.; Zhang, T.; Wu, T.; Yin, X.; Lang, Y.; Lu, H. The angiogenic effect of microRNA-21 targeting TIMP3 through the regulation of MMP2 and MMP9. PLoS ONE 2016, 11, e0149537. [Google Scholar] [CrossRef]
- Zhong, X.; Chung, A.C.K.; Chen, H.Y.; Dong, Y.; Meng, X.M.; Li, R.; Yang, W.; Hou, F.F.; Lan, H.Y. miR-21 Is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia 2013, 56, 663–674. [Google Scholar] [CrossRef]
- Wang, J.-Y.; Gao, Y.-B.; Zhang, N.; Zou, D.-W.; Wang, P.; Zhu, Z.-Y.; Li, J.-Y.; Zhou, S.-N.; Wang, S.-C.; Wang, Y.-Y.; et al. miR-21 Overexpression enhances TGF-β1-induced epithelial-to-mesenchymal transition by target smad7 and aggravates renal damage in diabetic nephropathy. Mol. Cell. Endocrinol. 2014, 392, 163–172. [Google Scholar] [CrossRef]
- Xu, X.; Song, N.; Zhang, X.; Jiao, X.; Hu, J.; Liang, M.; Teng, J.; Ding, X. Renal protection mediated by hypoxia inducible factor-1α depends on proangiogenesis function of miR-21 by targeting thrombospondin 1. Transplantation 2017, 101, 1811–1819. [Google Scholar] [CrossRef]
- Liu, X.; Hong, Q.; Wang, Z.; Yu, Y.; Zou, X.; Xu, L. MiR-21 inhibits autophagy by targeting Rab11a in renal ischemia/reperfusion. Exp. Cell Res. 2015, 338, 64–69. [Google Scholar] [CrossRef]
- Lai, J.Y.; Luo, J.; O’Connor, C.; Jing, X.; Nair, V.; Ju, W.; Randolph, A.; Ben-Dov, I.Z.; Matar, R.N.; Briskin, D.; et al. MicroRNA-21 in glomerular injury. J. Am. Soc. Nephrol. 2015, 26, 805–816. [Google Scholar] [CrossRef]
- Glowacki, F.; Savary, G.; Gnemmi, V.; Buob, D.; Van der Hauwaert, C.; Lo-Guidice, J.-M.; Bouyé, S.; Hazzan, M.; Pottier, N.; Perrais, M.; et al. Increased circulating miR-21 levels are associated with kidney fibrosis. PLoS ONE 2013, 8, e58014. [Google Scholar] [CrossRef]
- Hennino, M.-F.; Buob, D.; Van der Hauwaert, C.; Gnemmi, V.; Jomaa, Z.; Pottier, N.; Savary, G.; Drumez, E.; Noël, C.; Cauffiez, C.; et al. miR-21-5p Renal expression is associated with fibrosis and renal survival in patients with IgA nephropathy. Sci. Rep. 2016, 6, 27209. [Google Scholar] [CrossRef]
- Guo, J.; Song, W.; Boulanger, J.; Xu, E.Y.; Wang, F.; Zhang, Y.; He, Q.; Wang, S.; Yang, L.; Pryce, C.; et al. Dysregulated expression of microRNA-21 and disease related genes in human patients and mouse model of alport syndrome. Hum. Gene Ther. 2019. [Google Scholar] [CrossRef]
- Dey, N.; Ghosh-Choudhury, N.; Kasinath, B.S.; Choudhury, G.G. TGFβ-stimulated microrna-21 utilizes PTEN to orchestrate AKT/mTORC1 signaling for mesangial cell hypertrophy and matrix expansion. PLoS ONE 2012, 7, e42316. [Google Scholar] [CrossRef]
- Cheng, Y.; Zhu, P.; Yang, J.; Liu, X.; Dong, S.; Wang, X.; Chun, B.; Zhuang, J.; Zhang, C. Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4. Cardiovasc. Res. 2010, 87, 431–439. [Google Scholar] [CrossRef]
- Sims, E.K.; Lakhter, A.J.; Anderson-Baucum, E.; Kono, T.; Tong, X.; Evans-Molina, C. MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells. Diabetologia 2017, 60, 1057–1065. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Zhao, S.; Wu, D.; Liu, X.; Shi, M.; Wang, Y.; Zhang, F.; Ding, J.; Xiao, Y.; Guo, B. MicroRNA-22 promotes renal tubulointerstitial fibrosis by targeting PTEN and suppressing autophagy in diabetic nephropathy. J. Diabetes Res. 2018, 2018, 1–11. [Google Scholar] [CrossRef] [PubMed]
- He, F.; Peng, F.; Xia, X.; Zhao, C.; Luo, Q.; Guan, W.; Li, Z.; Yu, X.; Huang, F. MiR-135a promotes renal fibrosis in diabetic nephropathy by regulating TRPC1. Diabetologia 2014, 57, 1726–1736. [Google Scholar] [CrossRef] [PubMed]
- Zhou, H.; Hasni, S.A.; Perez, P.; Tandon, M.; Jang, S.-I.; Zheng, C.; Kopp, J.B.; Austin, H.; Balow, J.E.; Alevizos, I.; et al. miR-150 Promotes renal fibrosis in lupus nephritis by downregulating SOCS1. J. Am. Soc. Nephrol. 2013, 24, 1073–1087. [Google Scholar] [CrossRef] [PubMed]
- Xi, W.; Zhao, X.; Wu, M.; Jia, W.; Li, H. Lack of microRNA-155 ameliorates renal fibrosis by targeting PDE3A/TGF-β1/Smad signaling in mice with obstructive nephropathy. Cell Biol. Int. 2018, 42, 1523–1532. [Google Scholar] [CrossRef]
- XIE, S.; CHEN, H.; LI, F.; WANG, S.; GUO, J. Hypoxia-induced microRNA-155 promotes fibrosis in proximal tubule cells. Mol. Med. Rep. 2015, 11, 4555–4560. [Google Scholar] [CrossRef] [PubMed]
- Chen, B. The miRNA-184 drives renal fibrosis by targeting HIF1AN in vitro and in vivo. Int. Urol. Nephrol. 2019, 51, 543–550. [Google Scholar] [CrossRef]
- Bera, A.; Das, F.; Ghosh-Choudhury, N.; Mariappan, M.M.; Kasinath, B.S.; Ghosh Choudhury, G. Reciprocal regulation of miR-214 and PTEN by high glucose regulates renal glomerular mesangial and proximal tubular epithelial cell hypertrophy and matrix expansion. Am. J. Physiol. Physiol. 2017, 313, C430–C447. [Google Scholar] [CrossRef]
- Liu, M.; Liu, L.; Bai, M.; Zhang, L.; Ma, F.; Yang, X.; Sun, S. Hypoxia-induced activation of Twist/miR-214/E-cadherin axis promotes renal tubular epithelial cell mesenchymal transition and renal fibrosis. Biochem. Biophys. Res. Commun. 2018, 495, 2324–2330. [Google Scholar] [CrossRef]
- Zhu, X.; Li, W.; Li, H. miR-214 Ameliorates acute kidney injury via targeting DKK3 and activating of Wnt/β-catenin signaling pathway. Biol. Res. 2018, 51, 31. [Google Scholar] [CrossRef]
- Mu, J.; Pang, Q.; Guo, Y.-H.; Chen, J.-G.; Zeng, W.; Huang, Y.-J.; Zhang, J.; Feng, B. Functional implications of MicroRNA-215 in TGF-β1-induced phenotypic transition of mesangial cells by targeting CTNNBIP1. PLoS ONE 2013, 8, e58622. [Google Scholar] [CrossRef]
- Kato, M.; Wang, L.; Putta, S.; Wang, M.; Yuan, H.; Sun, G.; Lanting, L.; Todorov, I.; Rossi, J.J.; Natarajan, R. Post-transcriptional up-regulation of Tsc-22 by Ybx1, a target of miR-216a, mediates TGF-β-induced collagen expression in kidney cells. J. Biol. Chem. 2010, 285, 34004–34015. [Google Scholar] [CrossRef]
- Macconi, D.; Tomasoni, S.; Romagnani, P.; Trionfini, P.; Sangalli, F.; Mazzinghi, B.; Rizzo, P.; Lazzeri, E.; Abbate, M.; Remuzzi, G.; et al. MicroRNA-324-3p promotes renal fibrosis and is a target of ACE inhibition. J. Am. Soc. Nephrol. 2012, 23, 1496–1505. [Google Scholar] [CrossRef]
- Li, R.; Chung, A.C.K.; Dong, Y.; Yang, W.; Zhong, X.; Lan, H.Y. The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway. Kidney Int. 2013, 84, 1129–1144. [Google Scholar] [CrossRef]
- Alvarez, M.L.; Khosroheidari, M.; Eddy, E.; Kiefer, J. Role of MicroRNA 1207-5P and its host gene, the long non-coding RNA Pvt1, as mediators of extracellular matrix accumulation in the kidney: Implications for diabetic nephropathy. PLoS ONE 2013, 8, e77468. [Google Scholar] [CrossRef]
- Brennan, E.P.; Nolan, K.A.; Börgeson, E.; Gough, O.S.; McEvoy, C.M.; Docherty, N.G.; Higgins, D.F.; Murphy, M.; Sadlier, D.M.; Ali-Shah, S.T.; et al. Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGF β R1. J. Am. Soc. Nephrol. 2013, 24, 627–637. [Google Scholar] [CrossRef]
- Wang, B.; Jha, J.C.; Hagiwara, S.; McClelland, A.D.; Jandeleit-Dahm, K.; Thomas, M.C.; Cooper, M.E.; Kantharidis, P. Transforming growth factor-β1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b. Kidney Int. 2014, 85, 352–361. [Google Scholar] [CrossRef]
- Cushing, L.; Kuang, P.; Lü, J. The role of miR-29 in pulmonary fibrosis. Biochem. Cell Biol. 2015, 93, 109–118. [Google Scholar] [CrossRef]
- Meng, X.-M.; Tang, P.M.-K.; Li, J.; Lan, H.Y. TGF-Î2/Smad signaling in renal fibrosis. Front. Physiol. 2015, 6, 82. [Google Scholar] [CrossRef] [PubMed]
- Van Rooij, E.; Sutherland, L.B.; Thatcher, J.E.; DiMaio, J.M.; Naseem, R.H.; Marshall, W.S.; Hill, J.A.; Olson, E.N. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl. Acad. Sci. USA 2008, 105, 13027–13032. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Qin, W.; Chung, A.C.K.; Huang, X.R.; Meng, X.-M.; Hui, D.S.C.; Yu, C.-M.; Sung, J.J.Y.; Lan, H.Y. TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J. Am. Soc. Nephrol. 2011, 22, 1462–1474. [Google Scholar] [CrossRef] [PubMed]
- Ramdas, V.; McBride, M.; Denby, L.; Baker, A.H. Canonical transforming growth factor-β signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29. Am. J. Pathol. 2013, 183, 1885–1896. [Google Scholar] [CrossRef] [PubMed]
- Wang, B.; Komers, R.; Carew, R.; Winbanks, C.E.; Xu, B.; Herman-Edelstein, M.; Koh, P.; Thomas, M.; Jandeleit-Dahm, K.; Gregorevic, P.; et al. Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis. J. Am. Soc. Nephrol. 2012, 23, 252–265. [Google Scholar] [CrossRef] [PubMed]
- Hu, H.; Hu, S.; Xu, S.; Gao, Y.; Zeng, F.; Shui, H. miR-29b Regulates Ang II-induced EMT of rat renal tubular epithelial cells via targeting PI3K/AKT signaling pathway. Int. J. Mol. Med. 2018, 42, 453–460. [Google Scholar] [CrossRef] [PubMed]
- Long, J.; Wang, Y.; Wang, W.; Chang, B.H.J.; Danesh, F.R. MicroRNA-29c is a signature microrna under high glucose conditions that targets sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. J. Biol. Chem. 2011, 286, 11837–11848. [Google Scholar] [CrossRef] [PubMed]
- Hennemeier, I.; Humpf, H.-U.; Gekle, M.; Schwerdt, G. Role of microRNA-29b in the ochratoxin a-induced enhanced collagen formation in human kidney cells. Toxicology 2014, 324, 116–122. [Google Scholar] [CrossRef] [PubMed]
- Ben-Dov, I.Z.; Muthukumar, T.; Morozov, P.; Mueller, F.B.; Tuschl, T.; Suthanthiran, M. MicroRNA sequence profiles of human kidney allografts with or without tubulointerstitial fibrosis. Transplantation 2012, 94, 1086–1094. [Google Scholar] [CrossRef]
- Jiang, L.; Qiu, W.; Zhou, Y.; Wen, P.; Fang, L.; Cao, H.; Zen, K.; He, W.; Zhang, C.; Dai, C.; et al. A microRNA-30e/mitochondrial uncoupling protein 2 axis mediates TGF-β1-induced tubular epithelial cell extracellular matrix production and kidney fibrosis. Kidney Int. 2013, 84, 285–296. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Wang, J.; Duan, L.; Guo, T.; Gao, Y.; Tian, L.; Liu, J.; Wang, S.; Yang, J. Downregulation of miR-30c promotes renal fibrosis by target CTGF in diabetic nephropathy. J. Diabetes Complications 2016, 30, 406–414. [Google Scholar] [CrossRef]
- Morizane, R.; Fujii, S.; Monkawa, T.; Hiratsuka, K.; Yamaguchi, S.; Homma, K.; Itoh, H. miR-34c Attenuates epithelial-mesenchymal transition and kidney fibrosis with ureteral obstruction. Sci. Rep. 2015, 4, 4578. [Google Scholar] [CrossRef]
- Ning, Y.; Wang, X.; Wang, J.; Zeng, R.; Wang, G. miR-152 Regulates TGF-β1-induced epithelial-mesenchymal transition by targeting HPIP in tubular epithelial cells. Mol. Med. Rep. 2018, 17, 7973–7979. [Google Scholar] [CrossRef]
- Zhang, X.; Yang, Z.; Heng, Y.; Miao, C. MicroRNA-181 exerts an inhibitory role during renal fibrosis by targeting early growth response factor-1 and attenuating the expression of profibrotic markers. Mol. Med. Rep. 2019. [Google Scholar] [CrossRef]
- Shen, Y.; Zhao, Y.; Wang, L.; Zhang, W.; Liu, C.; Yin, A. MicroRNA-194 overexpression protects against hypoxia/reperfusion-induced HK-2 cell injury through direct targeting Rheb. J. Cell. Biochem. 2019, 120, 8311–8318. [Google Scholar] [CrossRef]
- Liu, F.; Zhang, Z.-P.; Xin, G.-D.; Guo, L.-H.; Jiang, Q.; Wang, Z.-X. miR-192 Prevents renal tubulointerstitial fibrosis in diabetic nephropathy by targeting Egr1. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 4252–4260. [Google Scholar]
- Wang, B.; Koh, P.; Winbanks, C.; Coughlan, M.T.; McClelland, A.; Watson, A.; Jandeleit-Dahm, K.; Burns, W.C.; Thomas, M.C.; Cooper, M.E.; et al. miR-200a Prevents renal fibrogenesis through repression of TGF-β2 expression. Diabetes 2011, 60, 280–287. [Google Scholar] [CrossRef]
- Oba, S.; Kumano, S.; Suzuki, E.; Nishimatsu, H.; Takahashi, M.; Takamori, H.; Kasuya, M.; Ogawa, Y.; Sato, K.; Kimura, K.; et al. miR-200b Precursor can ameliorate renal tubulointerstitial fibrosis. PLoS ONE 2010, 5, e13614. [Google Scholar] [CrossRef]
- Howe, E.N.; Cochrane, D.R.; Richer, J.K. The miR-200 and miR-221/222 microRNA families: Opposing effects on epithelial identity. J. Mammary Gland Biol. Neoplasia 2012, 17, 65–77. [Google Scholar] [CrossRef]
- Bai, J.; Xiao, X.; Zhang, X.; Cui, H.; Hao, J.; Han, J.; Cao, N. Erythropoietin inhibits hypoxia–induced epithelial-to-mesenchymal transition via upregulation of miR-200b in HK-2 cells. Cell. Physiol. Biochem. 2017, 42, 269–280. [Google Scholar] [CrossRef]
- Xiong, M.; Jiang, L.; Zhou, Y.; Qiu, W.; Fang, L.; Tan, R.; Wen, P.; Yang, J. The miR-200 family regulates TGF-β1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression. Am. J. Physiol. Physiol. 2012, 302, F369–F379. [Google Scholar] [CrossRef]
- Tang, O.; Chen, X.-M.; Shen, S.; Hahn, M.; Pollock, C.A. MiRNA-200b represses transforming growth factor-β1-induced EMT and fibronectin expression in kidney proximal tubular cells. Am. J. Physiol. Physiol. 2013, 304, F1266–F1273. [Google Scholar] [CrossRef][Green Version]
- Wu, J.; Liu, J.; Ding, Y.; Zhu, M.; Lu, K.; Zhou, J.; Xie, X.; Xu, Y.; Shen, X.; Chen, Y.; et al. MiR-455-3p suppresses renal fibrosis through repression of ROCK2 expression in diabetic nephropathy. Biochem. Biophys. Res. Commun. 2018, 503, 977–983. [Google Scholar] [CrossRef]
- Putta, S.; Lanting, L.; Sun, G.; Lawson, G.; Kato, M.; Natarajan, R. Inhibiting MicroRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J. Am. Soc. Nephrol. 2012, 23, 458–469. [Google Scholar] [CrossRef]
- Kato, M.; Zhang, J.; Wang, M.; Lanting, L.; Yuan, H.; Rossi, J.J.; Natarajan, R. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc. Natl. Acad. Sci. USA 2007, 104, 3432–3437. [Google Scholar] [CrossRef]
- Chung, A.C.K.; Huang, X.R.; Meng, X.; Lan, H.Y. miR-192 Mediates TGF-β/Smad3-driven renal fibrosis. J. Am. Soc. Nephrol. 2010, 21, 1317–1325. [Google Scholar] [CrossRef]
- Chung, A.C.K.; Dong, Y.; Yang, W.; Zhong, X.; Li, R.; Lan, H.Y. Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs. Mol. Ther. 2013, 21, 388–398. [Google Scholar] [CrossRef]
- Krupa, A.; Jenkins, R.; Luo, D.D.; Lewis, A.; Phillips, A.; Fraser, D. Loss of MicroRNA-192 promotes fibrogenesis in diabetic nephropathy. J. Am. Soc. Nephrol. 2010, 21, 438–447. [Google Scholar] [CrossRef]
- Wang, B.; Herman-Edelstein, M.; Koh, P.; Burns, W.; Jandeleit-Dahm, K.; Watson, A.; Saleem, M.; Goodall, G.J.; Twigg, S.M.; Cooper, M.E.; et al. E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta. Diabetes 2010, 59, 1794–1802. [Google Scholar] [CrossRef]
- Liu, G.; Friggeri, A.; Yang, Y.; Milosevic, J.; Ding, Q.; Thannickal, V.J.; Kaminski, N.; Abraham, E. miR-21 Mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J. Exp. Med. 2010, 207, 1589–1597. [Google Scholar] [CrossRef]
- Zhou, X.; Xu, H.; Liu, Z.; Wu, Q.; Zhu, R.; Liu, J. miR-21 Promotes cardiac fibroblast-to-myofibroblast transformation and myocardial fibrosis by targeting Jagged1. J. Cell. Mol. Med. 2018, 22, 3816–3824. [Google Scholar] [CrossRef]
- Krichevsky, A.M.; Gabriely, G. miR-21: A small multi-faceted RNA. J. Cell. Mol. Med. 2009, 13, 39–53. [Google Scholar] [CrossRef]
- Androsavich, J.R.; Chau, B.N.; Bhat, B.; Linsley, P.S.; Walter, N.G. Disease-linked microRNA-21 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver. RNA 2012, 18, 1510–1526. [Google Scholar] [CrossRef]
- Ma, L.; Yang, X.; Wei, R.; Ye, T.; Zhou, J.-K.; Wen, M.; Men, R.; Li, P.; Dong, B.; Liu, L.; et al. MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression. Cell Death Dis. 2018, 9, 718. [Google Scholar] [CrossRef]
- Sun, M.; Yu, H.; Zhang, Y.; Li, Z.; Gao, W. MicroRNA-214 mediates isoproterenol-induced proliferation and collagen synthesis in cardiac fibroblasts. Sci. Rep. 2016, 5, 18351. [Google Scholar] [CrossRef]
- Denby, L.; Ramdas, V.; Lu, R.; Conway, B.R.; Grant, J.S.; Dickinson, B.; Aurora, A.B.; McClure, J.D.; Kipgen, D.; Delles, C.; et al. MicroRNA-214 antagonism protects against renal fibrosis. J. Am. Soc. Nephrol. 2014, 25, 65–80. [Google Scholar] [CrossRef]
- Humphries, B.; Yang, C. The microRNA-200 family: Small molecules with novel roles in cancer development, progression and therapy. Oncotarget 2015, 6, 6472–6498. [Google Scholar] [CrossRef]
- Korpal, M.; Kang, Y. The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol. 2008, 5, 115–119. [Google Scholar] [CrossRef]
- Kriegel, A.J.; Liu, Y.; Fang, Y.; Ding, X.; Liang, M. The miR-29 family: Genomics, cell biology, and relevance to renal and cardiovascular injury. Physiol. Genomics 2012, 44, 237–244. [Google Scholar] [CrossRef]
- Huang, S.; Zhang, L.; Song, J.; Wang, Z.; Huang, X.; Guo, Z.; Chen, F.; Zhao, X. Long noncoding RNA MALAT1 mediates cardiac fibrosis in experimental postinfarct myocardium mice model. J. Cell. Physiol. 2019, 234, 2997–3006. [Google Scholar] [CrossRef]
- Yu, F.; Lu, Z.; Cai, J.; Huang, K.; Chen, B.; Li, G.; Dong, P.; Zheng, J. MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis. Cell Cycle 2015, 14, 3885–3896. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Zhang, K.; Han, X.; Zhang, Z.; Zheng, L.; Hu, Z.; Yao, Q.; Cui, H.; Shu, G.; Si, M.; Li, C.; et al. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways. Nat. Commun. 2017, 8, 144. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Zhang, Q.-Q.; Xu, M.-Y.; Qu, Y.; Hu, J.-J.; Li, Z.-H.; Zhang, Q.-D.; Lu, L.-G. TET3 mediates the activation of human hepatic stellate cells via modulating the expression of long non-coding RNA HIF1A-AS1. Int. J. Clin. Exp. Pathol. 2014, 7, 7744–7751. [Google Scholar]
- Lu, Q.; Guo, Z.; Xie, W.; Jin, W.; Zhu, D.; Chen, S.; Ren, T. The lncRNA H19 mediates pulmonary fibrosis by regulating the miR-196a/COL1A1 axis. Inflammation 2018, 41, 896–903. [Google Scholar] [CrossRef]
- Savary, G.; Dewaeles, E.; Diazzi, S.; Buscot, M.; Nottet, N.; Fassy, J.; Courcot, E.; Henaoui, I.-S.; Lemaire, J.; Martis, N.; et al. The long non-coding RNA DNM3OS is a reservoir of fibromirs with major functions in lung fibroblast response to TGF-β and pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2019. [Google Scholar] [CrossRef] [PubMed]
- Han, R.; Hu, S.; Qin, W.; Shi, J.; Zeng, C.; Bao, H.; Liu, Z. Upregulated long noncoding RNA LOC105375913 induces tubulointerstitial fibrosis in focal segmental glomerulosclerosis. Sci. Rep. 2019, 9, 716. [Google Scholar] [CrossRef] [PubMed]
- Chen, W.; Zhou, Z.-Q.; Ren, Y.-Q.; Zhang, L.; Sun, L.-N.; Man, Y.-L.; Wang, Z.-K. Effects of long non-coding RNA LINC00667 on renal tubular epithelial cell proliferation, apoptosis and renal fibrosis via the miR-19b-3p/LINC00667/CTGF signaling pathway in chronic renal failure. Cell. Signal. 2019, 54, 102–114. [Google Scholar] [CrossRef]
- Huang, S.; Xu, Y.; Ge, X.; Xu, B.; Peng, W.; Jiang, X.; Shen, L.; Xia, L. Long noncoding RNA NEAT1 accelerates the proliferation and fibrosis in diabetic nephropathy through activating Akt/mTOR signaling pathway. J. Cell. Physiol. 2019, 234, 11200–11207. [Google Scholar] [CrossRef]
- Wang, P.; Luo, M.-L.; Song, E.; Zhou, Z.; Ma, T.; Wang, J.; Jia, N.; Wang, G.; Nie, S.; Liu, Y.; et al. Long noncoding RNA lnc-TSI inhibits renal fibrogenesis by negatively regulating the TGF-β/Smad3 pathway. Sci. Transl. Med. 2018, 10, eaat2039. [Google Scholar] [CrossRef]
- Liang, Y.-J.; Wang, Q.-Y.; Zhou, C.-X.; Yin, Q.-Q.; He, M.; Yu, X.-T.; Cao, D.-X.; Chen, G.-Q.; He, J.-R.; Zhao, Q. MiR-124 targets Slug to regulate epithelial–mesenchymal transition and metastasis of breast cancer. Carcinogenesis 2013, 34, 713–722. [Google Scholar] [CrossRef] [PubMed]
- Jiang, L.; Lin, T.; Xu, C.; Hu, S.; Pan, Y.; Jin, R. miR-124 Interacts with the Notch1 signalling pathway and has therapeutic potential against gastric cancer. J. Cell. Mol. Med. 2016, 20, 313–322. [Google Scholar] [CrossRef]
- Chen, W.; Zhang, L.; Zhou, Z.-Q.; Ren, Y.-Q.; Sun, L.-N.; Man, Y.-L.; Ma, Z.-W.; Wang, Z.-K. Effects of long non-coding RNA LINC00963 on renal interstitial fibrosis and oxidative stress of rats with chronic renal failure via the foxo signaling pathway. Cell. Physiol. Biochem. 2018, 46, 815–828. [Google Scholar] [CrossRef]
- Zhou, S.-G.; Zhang, W.; Ma, H.-J.; Guo, Z.-Y.; Xu, Y. Silencing of LncRNA TCONS_00088786 reduces renal fibrosis through miR-132. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 166–173. [Google Scholar]
- Zhou, Q.; Chung, A.C.K.; Huang, X.R.; Dong, Y.; Yu, X.; Lan, H.Y. Identification of novel long noncoding RNAs associated with TGF-β/Smad3-mediated renal inflammation and fibrosis by RNA sequencing. Am. J. Pathol. 2014, 184, 409–417. [Google Scholar] [CrossRef]
- Feng, M.; Tang, P.M.-K.; Huang, X.-R.; Sun, S.-F.; You, Y.-K.; Xiao, J.; Lv, L.-L.; Xu, A.-P.; Lan, H.-Y. TGF-β mediates renal fibrosis via the Smad3-Erbb4-IR long noncoding RNA axis. Mol. Ther. 2018, 26, 148–161. [Google Scholar] [CrossRef]
- Sun, S.F.; Tang, P.M.K.; Feng, M.; Xiao, J.; Huang, X.R.; Li, P.; Ma, R.C.W.; Lan, H.Y. Novel lncRNA Erbb4-IR promotes diabetic kidney injury in db/db mice by targeting miR-29b. Diabetes 2018, 67, 731–744. [Google Scholar] [CrossRef]
- Zhang, C.; Yuan, J.; Hu, H.; Chen, W.; Liu, M.; Zhang, J.; Sun, S.; Guo, Z. Long non-coding RNA CHCHD4P4 promotes epithelial-mesenchymal transition and inhibits cell proliferation in calcium oxalate-induced kidney damage. Braz. J. Med. Biol. Res. 2017, 51, e6536. [Google Scholar] [CrossRef]
- Sun, J.; Zhang, S.; Shi, B.; Zheng, D.; Shi, J. Transcriptome identified lncRNAs associated with renal fibrosis in UUO rat model. Front. Physiol. 2017, 8, 658. [Google Scholar] [CrossRef]
- Gao, Y.; Chen, Z.-Y.; Wang, Y.; Liu, Y.; Ma, J.-X.; Li, Y.-K. Long non-coding RNA ASncmtRNA-2 is upregulated in diabetic kidneys and high glucose-treated mesangial cells. Exp. Ther. Med. 2017, 13, 581–587. [Google Scholar] [CrossRef][Green Version]
- Zhang, H.; Sun, S.-C. NF-κB in inflammation and renal diseases. Cell Biosci. 2015, 5, 63. [Google Scholar] [CrossRef]
- Yi, H.; Peng, R.; Zhang, L.; Sun, Y.; Peng, H.; Liu, H.; Yu, L.; Li, A.; Zhang, Y.; Jiang, W.; et al. LincRNA-Gm4419 knockdown ameliorates NF-κB/NLRP3 inflammasome-mediated inflammation in diabetic nephropathy. Cell Death Dis. 2017, 8, e2583. [Google Scholar] [CrossRef]
- Xie, H.; Xue, J.-D.; Chao, F.; Jin, Y.-F.; Fu, Q.; Xie, H.; Xue, J.-D.; Chao, F.; Jin, Y.-F.; Fu, Q. Long non-coding RNA-H19 antagonism protects against renal fibrosis. Oncotarget 2016, 7, 51473–51481. [Google Scholar] [CrossRef][Green Version]
- Arvaniti, E.; Moulos, P.; Vakrakou, A.; Chatziantoniou, C.; Chadjichristos, C.; Kavvadas, P.; Charonis, A.; Politis, P.K. Whole-transcriptome analysis of UUO mouse model of renal fibrosis reveals new molecular players in kidney diseases. Sci. Rep. 2016, 6, 26235. [Google Scholar] [CrossRef][Green Version]
- Zhou, Q.; Huang, X.R.; Yu, J.; Yu, X.; Lan, H.Y. Long noncoding RNA Arid2-IR is a novel therapeutic target for renal inflammation. Mol. Ther. 2015, 23, 1034–1043. [Google Scholar] [CrossRef]
- Gao, J.; Wang, W.; Wang, F.; Guo, C. LncRNA-NR_033515 promotes proliferation, fibrogenesis and epithelial-to-mesenchymal transition by targeting miR-743b-5p in diabetic nephropathy. Biomed. Pharmacother. 2018, 106, 543–552. [Google Scholar] [CrossRef]
- Hu, M.; Wang, R.; Li, X.; Fan, M.; Lin, J.; Zhen, J.; Chen, L.; Lv, Z. LncRNA MALAT1 is dysregulated in diabetic nephropathy and involved in high glucose-induced podocyte injury via its interplay with β-catenin. J. Cell. Mol. Med. 2017, 21, 2732–2747. [Google Scholar] [CrossRef]
- Feng, Y.; Chen, S.; Xu, J.; Zhu, Q.; Ye, X.; Ding, D.; Yao, W.; Lu, Y.; Ye, X.; Ye, X.; et al. Dysregulation of lncRNAs GM5524 and GM15645 involved in high-glucose-induced podocyte apoptosis and autophagy in diabetic nephropathy. Mol. Med. Rep. 2018, 18, 3657–3664. [Google Scholar] [CrossRef]
- Polovic, M.; Dittmar, S.; Hennemeier, I.; Humpf, H.-U.; Seliger, B.; Fornara, P.; Theil, G.; Azinovic, P.; Nolze, A.; Köhn, M.; et al. Identification of a novel lncRNA induced by the nephrotoxin ochratoxin A and expressed in human renal tumor tissue. Cell. Mol. Life Sci. 2018, 75, 2241–2256. [Google Scholar] [CrossRef]
- Wang, M.; Wang, S.; Yao, D.; Yan, Q.; Lu, W. A novel long non-coding RNA CYP4B1-PS1-001 regulates proliferation and fibrosis in diabetic nephropathy. Mol. Cell. Endocrinol. 2016, 426, 136–145. [Google Scholar] [CrossRef]
- Wang, S.; Chen, X.; Wang, M.; Yao, D.; Chen, T.; Yan, Q.; Lu, W. Long non-coding RNA CYP4B1-PS1-001 inhibits proliferation and fibrosis in diabetic nephropathy by interacting with Nucleolin. Cell. Physiol. Biochem. 2018, 49, 2174–2187. [Google Scholar] [CrossRef]
- Wang, M.; Yao, D.; Wang, S.; Yan, Q.; Lu, W. Long non-coding RNA ENSMUST00000147869 protects mesangial cells from proliferation and fibrosis induced by diabetic nephropathy. Endocrine 2016, 54, 81–92. [Google Scholar] [CrossRef]
- Li, A.; Peng, R.; Sun, Y.; Liu, H.; Peng, H.; Zhang, Z. LincRNA 1700020I14Rik alleviates cell proliferation and fibrosis in diabetic nephropathy via miR-34a-5p/Sirt1/HIF-1α signaling. Cell Death Dis. 2018, 9, 461. [Google Scholar] [CrossRef]
- Xue, R.; Li, Y.; Li, X.; Ma, J.; An, C.; Ma, Z. miR-185 Affected the EMT, cell viability and proliferation via DNMT1/MEG3 pathway in TGF-β1-induced renal fibrosis. Cell Biol. Int. 2018. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; Pang, J.; Li, H.; Long, J.; Fang, F.; Chen, J.; Zhu, X.; Xiang, X.; Zhang, D. lncRNA ZEB1-AS1 was suppressed by p53 for renal fibrosis in diabetic nephropathy. Mol. Ther. Nucleic Acids 2018, 12, 741–750. [Google Scholar] [CrossRef] [PubMed]
- Xiao, X.; Yuan, Q.; Chen, Y.; Huang, Z.; Fang, X.; Zhang, H.; Peng, L.; Xiao, P. LncRNA ENST00000453774.1 contributes to oxidative stress defense dependent on autophagy mediation to reduce extracellular matrix and alleviate renal fibrosis. J. Cell. Physiol. 2018, 234, 9130–9143. [Google Scholar] [CrossRef]
- Hajjari, M.; Salavaty, A. HOTAIR: An oncogenic long non-coding RNA in different cancers. Cancer Biol. Med. 2015, 12, 1–9. [Google Scholar]
- Zhou, H.; Gao, L.; Yu, Z.; Hong, S.; Zhang, Z.; Qiu, Z. LncRNA HOTAIR promotes renal interstitial fibrosis by regulating Notch1 pathway via the modulation of miR-124. Nephrology 2018. [Google Scholar] [CrossRef] [PubMed]
- Zhou, H.; Qiu, Z.-Z.; Yu, Z.-H.; Gao, L.; He, J.-M.; Zhang, Z.-W.; Zheng, J. Paeonol reverses promoting effect of the HOTAIR/miR-124/Notch1 axis on renal interstitial fibrosis in a rat model. J. Cell. Physiol. 2019. [Google Scholar] [CrossRef]
- Van Rooij, E.; Kauppinen, S. Development of microRNA therapeutics is coming of age. EMBO Mol. Med. 2014, 6, 851–864. [Google Scholar] [CrossRef][Green Version]
- Chiu, Y.-L.; Rana, T.M. siRNA function in RNAi: A chemical modification analysis. RNA 2003, 9, 1034–1048. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Chen, P.Y.; Weinmann, L.; Gaidatzis, D.; Pei, Y.; Zavolan, M.; Tuschl, T.; Meister, G. Strand-specific 5′-O-methylation of siRNA duplexes controls guide strand selection and targeting specificity. RNA 2008, 14, 263–274. [Google Scholar] [CrossRef]
- Michelfelder, S.; Trepel, M. Adeno-associated viral vectors and their redirection to cell-type specific receptors. Adv. Genet. 2009, 67, 29–60. [Google Scholar] [PubMed]
- Montgomery, R.L.; Yu, G.; Latimer, P.A.; Stack, C.; Robinson, K.; Dalby, C.M.; Kaminski, N.; van Rooij, E. MicroRNA mimicry blocks pulmonary fibrosis. EMBO Mol. Med. 2014, 6, 1347–1356. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Chakraborty, C.; Sharma, A.R.; Sharma, G.; Doss, C.G.P.; Lee, S.-S. Therapeutic miRNA and siRNA: Moving from bench to clinic as next generation medicine. Mol. Ther. Nucleic Acids 2017, 8, 132–143. [Google Scholar] [CrossRef] [PubMed]
- Lennox, K.A.; Behlke, M.A. Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther. 2011, 18, 1111–1120. [Google Scholar] [CrossRef] [PubMed]
- Louloupi, A.; Ørom, U.A.V. Inhibiting pri-miRNA processing with target site blockers. Methods Mol. Biol. 2018, 1823, 63–68. [Google Scholar] [PubMed]
- Knauss, J.L.; Bian, S.; Sun, T. Plasmid-based target protectors allow specific blockade of miRNA silencing activity in mammalian developmental systems. Front. Cell. Neurosci. 2013, 7, 163. [Google Scholar] [CrossRef] [PubMed]
- Kölling, M.; Kaucsar, T.; Schauerte, C.; Hübner, A.; Dettling, A.; Park, J.-K.; Busch, M.; Wulff, X.; Meier, M.; Scherf, K.; et al. Therapeutic miR-21 silencing ameliorates diabetic kidney disease in mice. Mol. Ther. 2017, 25, 165–180. [Google Scholar] [CrossRef]
- Gomez, I.G.; MacKenna, D.A.; Johnson, B.G.; Kaimal, V.; Roach, A.M.; Ren, S.; Nakagawa, N.; Xin, C.; Newitt, R.; Pandya, S.; et al. Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J. Clin. Invest. 2015, 125, 141–156. [Google Scholar] [CrossRef] [PubMed]
- Creemers, E.E.; van Rooij, E. Function and therapeutic potential of noncoding RNAs in cardiac fibrosis. Circ. Res. 2016, 118, 108–118. [Google Scholar] [CrossRef]
- Bonetti, A.; Carninci, P. From bench to bedside: The long journey of long non-coding RNAs. Curr. Opin. Syst. Biol. 2017, 3, 119–124. [Google Scholar] [CrossRef]
- Hagedorn, P.H.; Pontoppidan, M.; Bisgaard, T.S.; Berrera, M.; Dieckmann, A.; Ebeling, M.; Møller, M.R.; Hudlebusch, H.; Jensen, M.L.; Hansen, H.F.; et al. Identifying and avoiding off-target effects of RNase H-dependent antisense oligonucleotides in mice. Nucleic Acids Res. 2018, 46, 5366–5380. [Google Scholar] [CrossRef]
- Kato, M.; Wang, M.; Chen, Z.; Bhatt, K.; Oh, H.J.; Lanting, L.; Deshpande, S.; Jia, Y.; Lai, J.Y.C.; O’Connor, C.L.; et al. An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat. Commun. 2016, 7, 12864. [Google Scholar] [CrossRef][Green Version]
- Li, C.H.; Chen, Y. Targeting long non-coding RNAs in cancers: Progress and prospects. Int. J. Biochem. Cell Biol. 2013, 45, 1895–1910. [Google Scholar] [CrossRef]
- Prasad, N.; Kumar, S.; Manjunath, R.; Bhadauria, D.; Kaul, A.; Sharma, R.K.; Gupta, A.; Lal, H.; Jain, M.; Agrawal, V. Real-time ultrasound-guided percutaneous renal biopsy with needle guide by nephrologists decreases post-biopsy complications. Clin. Kidney J. 2015, 8, 151–156. [Google Scholar] [CrossRef]
- Schwab, S.; Marwitz, T.; Woitas, R.P. The role of prognostic assessment with biomarkers in chronic kidney disease: A narrative review. J. Lab. Precis. Med. 2018, 3, 12. [Google Scholar] [CrossRef]
- Weber, J.A.; Baxter, D.H.; Zhang, S.; Huang, D.Y.; How Huang, K.; Jen Lee, M.; Galas, D.J.; Wang, K. The microRNA spectrum in 12 body fluids. Clin. Chem. 2010, 56, 1733–1741. [Google Scholar] [CrossRef]
- Mitchell, P.S.; Parkin, R.K.; Kroh, E.M.; Fritz, B.R.; Wyman, S.K.; Pogosova-Agadjanyan, E.L.; Peterson, A.; Noteboom, J.; O’Briant, K.C.; Allen, A.; et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008, 105, 10513–10518. [Google Scholar] [CrossRef][Green Version]
- Bolha, L.; Ravnik-Glavač, M.; Glavač, D. Long noncoding RNAs as biomarkers in cancer. Dis. Markers 2017, 2017, 7243968. [Google Scholar] [CrossRef]
- Cheng, L.; Sun, X.; Scicluna, B.J.; Coleman, B.M.; Hill, A.F. Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int. 2014, 86, 433–444. [Google Scholar] [CrossRef]
- Cardenas-Gonzalez, M.; Srivastava, A.; Pavkovic, M.; Bijol, V.; Rennke, H.G.; Stillman, I.E.; Zhang, X.; Parikh, S.; Rovin, B.H.; Afkarian, M.; et al. Identification, confirmation, and replication of novel urinary microRNA biomarkers in lupus nephritis and diabetic nephropathy. Clin. Chem. 2017, 63, 1515–1526. [Google Scholar] [CrossRef] [PubMed]
- Ramachandran, K.; Saikumar, J.; Bijol, V.; Koyner, J.L.; Qian, J.; Betensky, R.A.; Waikar, S.S.; Vaidya, V.S. Human miRNome profiling identifies microRNAs differentially present in the urine after kidney injury. Clin. Chem. 2013, 59, 1742–1752. [Google Scholar] [CrossRef] [PubMed]
- Sonoda, H.; Lee, B.R.; Park, K.-H.; Nihalani, D.; Yoon, J.-H.; Ikeda, M.; Kwon, S.-H. miRNA Profiling of urinary exosomes to assess the progression of acute kidney injury. Sci. Rep. 2019, 9, 4692. [Google Scholar] [CrossRef] [PubMed]
- Khurana, R.; Ranches, G.; Schafferer, S.; Lukasser, M.; Rudnicki, M.; Mayer, G.; Hüttenhofer, A. Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease. RNA 2017, 23, 142–152. [Google Scholar] [CrossRef]
- Chen, C.; Lu, C.; Qian, Y.; Li, H.; Tan, Y.; Cai, L.; Weng, H. Urinary miR-21 as a potential biomarker of hypertensive kidney injury and fibrosis. Sci. Rep. 2017, 7, 17737. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Lv, L.-L.; Cao, Y.-H.; Ni, H.-F.; Xu, M.; Liu, D.; Liu, H.; Chen, P.-S.; Liu, B.-C. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am. J. Physiol. Physiol. 2013, 305, F1220–F1227. [Google Scholar] [CrossRef][Green Version]
- Zununi Vahed, S.; Omidi, Y.; Ardalan, M.; Samadi, N. Dysregulation of urinary miR-21 and miR-200b associated with interstitial fibrosis and tubular atrophy (IFTA) in renal transplant recipients. Clin. Biochem. 2017, 50, 32–39. [Google Scholar] [CrossRef]
- Zhou, H.; Cheruvanky, A.; Hu, X.; Matsumoto, T.; Hiramatsu, N.; Cho, M.E.; Berger, A.; Leelahavanichkul, A.; Doi, K.; Chawla, L.S.; et al. Urinary exosomal transcription factors, a new class of biomarkers for renal disease. Kidney Int. 2008, 74, 613–621. [Google Scholar] [CrossRef][Green Version]
- Zununi Vahed, S.; Poursadegh Zonouzi, A.; Ghanbarian, H.; Ghojazadeh, M.; Samadi, N.; Ardalan, M. Upregulated expression of circulating microRNAs in kidney transplant recipients with interstitial fibrosis and tubular atrophy. Iran. J. Kidney Dis. 2017, 11, 309–318. [Google Scholar]
- Muralidharan, J.; Ramezani, A.; Hubal, M.; Knoblach, S.; Shrivastav, S.; Karandish, S.; Scott, R.; Maxwell, N.; Ozturk, S.; Beddhu, S.; et al. Extracellular microRNA signature in chronic kidney disease. Am. J. Physiol. Renal Physiol. 2017, 312, F982–F991. [Google Scholar] [CrossRef]
- Poel, D.; Buffart, T.E.; Oosterling-Jansen, J.; Verheul, H.M.; Voortman, J. Evaluation of several methodological challenges in circulating miRNA qPCR studies in patients with head and neck cancer. Exp. Mol. Med. 2018, 50, e454. [Google Scholar] [CrossRef][Green Version]
- Nair, V.S.; Pritchard, C.C.; Tewari, M.; Ioannidis, J.P.A. Design and analysis for studying microRNAs in human disease: A primer on -omic technologies. Am. J. Epidemiol. 2014, 180, 140–152. [Google Scholar] [CrossRef]
- Haider, B.A.; Baras, A.S.; McCall, M.N.; Hertel, J.A.; Cornish, T.C.; Halushka, M.K. A critical evaluation of microRNA biomarkers in non-neoplastic disease. PLoS ONE 2014, 9, e89565. [Google Scholar] [CrossRef]
- Ma, J.; Li, N.; Guarnera, M.; Jiang, F. Quantification of plasma miRNAs by digital PCR for cancer diagnosis. Biomark. Insights 2013, 8, 127–136. [Google Scholar] [CrossRef]
- Hindson, C.M.; Chevillet, J.R.; Briggs, H.A.; Gallichotte, E.N.; Ruf, I.K.; Hindson, B.J.; Vessella, R.L.; Tewari, M. Absolute quantification by droplet digital PCR versus analog real-time PCR. Nat. Methods 2013, 10, 1003–1005. [Google Scholar] [CrossRef][Green Version]
- Mohankumar, S.; Patel, T. Extracellular vesicle long noncoding RNA as potential biomarkers of liver cancer. Brief. Funct. Genomics 2016, 15, 249–256. [Google Scholar] [CrossRef]
Figure 1. Classification and function of non-coding RNAs (ncRNAs).
Figure 2. Classification of long non-coding RNAs (lncRNAs) according to their genomic location. (a) Intergenic lncRNAs are located between two coding genes; (b) intronic lncRNAs are transcribed entirely from introns of protein-coding genes; (c) antisense lncRNAs are transcribed from the antisense strand of a coding gene and overlap at least one exon; (d) bidirectional lncRNAs are localized within 1 kb of the promoter of a coding gene and oriented in the other direction; (e) enhancer lncRNAs are located in enhancer regions associated with a coding gene. Arrows indicate the direction of transcription.
Figure 3. General mechanisms of non-coding RNAs involved in kidney fibrosis.
Table 1. Summary of miRNAs involved in renal fibrosis.
|Up||miR-21||Renal tissues from kidney transplanted patients|
Renal tissues from patients with IgA nephropathy
Renal tissues from patients with Alport Syndrome
UUO mouse model
DN mouse model
Ichemia reperfusion mouse model
|PTEN, SMAD7, PPARA, PDCD4, BCL2, PHD2, MKK3, RECK, TIMP3, THSP1, RAB11A||[41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63]|
|miR-22||DN rat model|
|miR-135a||Serum and renal tissues from patients with DN|
DN mouse model
|miR-150||renal tissue from patients with lupus nephritis|
|miR-155||UUO mouse model|
|miR-184||UUO mouse models|
|miR-214||UUO mouse model|
DN mouse model
|DKK3, CDH1, PTEN||[70,71,72]|
|miR-215||DN mouse model|
|miR-216a||DN mouse model|
|miR-324||Rat model of nephropathy (Munich Wistar Fromter rats)|
|miR-433||UUO mouse model|
|G6PD, PMEPAI1, PDK1, SMAD7|||
|Down||let-7 family||DN mouse model|
|miR-29 family||UUO mouse model|
Adenine gavage in mice
Chronic renal failure rat model (5/6e nephrectomy)
DN mouse model
HEK293 treated with ochratoxin A
|COL, FN1, AGT, ADAM12, ADAM19, PIK3R2||[80,81,82,83,84,85,86,87,88]|
|miR-30||Renal tissues from kidney transplanted patients|
UUO mouse model
DN mouse model
|CTGF, KLF11, UCP2||[89,90,91]|
|miR-34 family||UUO mouse model|
|miR-181||UUO mouse model||EGR1|||
|miR-194||Ischemia reperfusion mouse model|
|miR-200 family||UUO mouse model|
Adenine gavage in mice
|miR-455||DN rat model|
|miR-192||UUO mouse model|
DN mouse model
IgA nephropathy mouse model
Abbreviations: UUO (ureteral unilateral obstruction); RPTEC (renal proximal tubular epithelial cells); DN (diabetic nephropathy).
Table 2. LncRNAs involved in kidney fibrosis.
|Up||LOC105375913||Renal tissue of patients with segmental glomeruloscleoris|
|Binding to miR-27b and leading to Snail expression||Pro-fibrotic|||
|LINC00667||Renal tissue of patients with chronic renal failure|
Chronic renal failure rat model (partial nephrectomy)
|Binding to Ago2, targeting miR-19b-3p||Pro-fibrotic|||
|NEAT1||DN rat model|
|Pro-fibrotic and increase of proliferation|||
UUO mouse model
Ischemia-reperfusion mouse model
Renal tissue of patients with IgA nephropathy
|Synergic binding to Smad3||Anti-fibrotic|||
|HOTAIR||UUO rat model|
|Acting as a ceRNA with miR-124: activation of Jagged1/Nocth1 signaling||Pro-fibrotic||[130,131]|
|LINC00963||Chronic renal failure rat model (5/6e nephrectomy)||Inhibition of FoxO signaling pathway by targeting FoxO3a||Pro-fibrotic|||
|TCONS_00088786||UUO mouse model|
|Possibly regulation of miR-132 expression||Pro-fibrotic|||
|UUO mouse model|
Anti GBM mouse model
DN mouse model
|Downstream of TGFb/Smad3 pathway by binding Smad7 gene|
Binding to miR-29b
|CHCHD4P4||Stone kidney mouse model|
|TCONS_00088786||UUO rat model|
|TCONS_01496394||UUO rat model|
|ASncmtRNA-2||DN mouse model|
|LincRNA-Gm4419||DN mouse model|
|Activation of NFkB/NLRP3 pathway by interacting with p50||Pro-fibrotic and pro-inflammatory||[140,141]|
|H19||UUO mouse model|
|Acting as a ceRNA with miR-17 and fibronectin mRNA||Pro-fibrotic|||
|RP23.45G16.5||UUO mouse model|
|AI662270||UUO mouse model|
|No significative effect|||
|UUO mouse model|
|Smad3 binding site in Arid2-IR promoter|
Promoting NF-κB signaling
|Pro-fibrotic and pro-inflammatory effects|||
|np-17856||UUO mouse model|
Glomerulonephritis mouse model
|Smad3 binding site||Pro-fibrotic and pro-inflammatory|||
|NR_033515||Serum of patients with diabetic nephropathy|
|Targeting miR-743b-5p||Pro-fibrotic and promotes proliferation|||
|MALAT1||DN mouse model|
|Binding to SRSF1|
|Gm5524||DN mouse model|
|Autophagy increase and apoptosis decrease|||
|WISP1-AS1||RPTEC cells||Modulating ochratoxin-A-induced Egr-1 and E2F activities||Cell viability increase|||
|Down||Gm15645||DN mouse model|
|Autophagy decrease and apoptosis increase|||
|DN mouse model|
|Enhancing ubiquitination and degradation of nucleolin||Anti-fibrotic and anti-proliferative||[149,150]|
|3110045C21Rik||UUO mouse model|
|ENSMUST00000147869||DN mouse model|
|Associated with Cyp4a12a||Anti-fibrotic and anti-proliferative|||
|DN mouse model|
|Binding to miR-34a-5p. Inhibition of Sirt1/ HIF-1α signal pathway by targeting miR-34a-5p.||Anti-fibrotic|||
|ZEB1-AS1||DN mouse model|
|Promoting Zeb1 expression by binding H3K4 Methyltransferase MLL1||Anti-fibrotic|||
|ENST00000453774.1||Renal tissue of patients with renal fibrosis|
UUO mouse model
Note: Studies in bold are mechanistic studies. Abbreviations: UUO (ureteral unilateral obstruction); RPTEC (renal proximal tubular epithelial cells); DN (diabetic nephropathy)
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).