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• W2896724865 abstract "Acute kidney injury (AKI) is an important health issue concerning ∼50% of patients treated in intensive care units. AKI mainly occurs after sepsis, acute ischemia, nephrotoxicity, or hypoxia and leads to severe damage of the kidney and to an increased risk of mortality. The diagnosis of AKI is currently based on creatinine urea levels and diuresis. Yet, novel markers may improve the accuracy of this diagnosis at an early stage of the disease, thereby allowing early prevention and therapy, ultimately leading to a reduction in the need for renal replacement therapy and decreased mortality. Non–protein-coding RNAs or noncoding RNAs are central players in development and disease. They are important regulatory molecules that allow a fine-tuning of gene expression and protein synthesis. This regulation is necessary to maintain homeostasis, and its dysregulation is often associated with disease development. Noncoding RNAs are present in the kidney and in body fluids and their expression is modulated during AKI. This review article assembles the current knowledge of the role of noncoding RNAs, including microRNAs, long noncoding RNAs and circular RNAs, in the pathogenesis of AKI. Their potential as biomarkers and therapeutic targets as well as the challenges to translate research findings to clinical application are discussed. Although microRNAs have entered clinical testing, preclinical and clinical trials are needed before long noncoding RNAs and circular RNAs may be considered as useful biomarkers or therapeutic targets of AKI. Acute kidney injury (AKI) is an important health issue concerning ∼50% of patients treated in intensive care units. AKI mainly occurs after sepsis, acute ischemia, nephrotoxicity, or hypoxia and leads to severe damage of the kidney and to an increased risk of mortality. The diagnosis of AKI is currently based on creatinine urea levels and diuresis. Yet, novel markers may improve the accuracy of this diagnosis at an early stage of the disease, thereby allowing early prevention and therapy, ultimately leading to a reduction in the need for renal replacement therapy and decreased mortality. Non–protein-coding RNAs or noncoding RNAs are central players in development and disease. They are important regulatory molecules that allow a fine-tuning of gene expression and protein synthesis. This regulation is necessary to maintain homeostasis, and its dysregulation is often associated with disease development. Noncoding RNAs are present in the kidney and in body fluids and their expression is modulated during AKI. This review article assembles the current knowledge of the role of noncoding RNAs, including microRNAs, long noncoding RNAs and circular RNAs, in the pathogenesis of AKI. Their potential as biomarkers and therapeutic targets as well as the challenges to translate research findings to clinical application are discussed. Although microRNAs have entered clinical testing, preclinical and clinical trials are needed before long noncoding RNAs and circular RNAs may be considered as useful biomarkers or therapeutic targets of AKI. In 2012 the Kidney Disease Improving Global Outcomes (KDIGO) released the guidelines for AKI.1Section 2: AKI definition.Kidney Int Suppl. 2012; 2: 19-36Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The definition of AKI focuses on serum creatinine levels and urine output (Table 1). If AKI persists for >7 days, it is called acute kidney disease.2Chawla L.S. Bellomo R. Bihorac A. et al.Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.Nat Rev Nephrol. 2017; 13: 241-257Crossref PubMed Scopus (0) Google Scholar AKI occurs in up to 50% of patients in intensive care units.2Chawla L.S. Bellomo R. Bihorac A. et al.Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.Nat Rev Nephrol. 2017; 13: 241-257Crossref PubMed Scopus (0) Google Scholar, 3Hoste E.A. Bagshaw S.M. Bellomo R. et al.Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study.Intensive Care Med. 2015; 41: 1411-1423Crossref PubMed Scopus (306) Google Scholar The main reasons for AKI are infections/sepsis, ischemia, nephrotoxicity, and hypoxia, which lead to subsequent organ damage to the kidney. Several risk factors for the development of AKI have been identified (Table 2). AKI complicates patient recovery because of volume overload, electrolyte disorders, drug toxicity, or uremia. It is furthermore associated with an increased rate of cardiovascular events4Chawla L.S. Amdur R.L. Shaw A.D. et al.Association between AKI and long-term renal and cardiovascular outcomes in United States veterans.Clin J Am Soc Nephrol. 2014; 9: 448-456Crossref PubMed Scopus (117) Google Scholar and the development of chronic kidney disease.5Chawla L.S. Eggers P.W. Star R.A. et al.Acute kidney injury and chronic kidney disease as interconnected syndromes.N Engl J Med. 2014; 371: 58-66Crossref PubMed Scopus (400) Google Scholar, 6Venkatachalam M.A. Griffin K.A. Lan R. et al.Acute kidney injury: a springboard for progression in chronic kidney disease.Am J Physiol Renal Physiol. 2010; 298: F1078-F1094Crossref PubMed Scopus (271) Google Scholar AKI is accompanied by an increased risk of morbidity and mortality in critically ill patients.Table 1Stages of AKIModified from Kidney Int Suppl.1Section 2: AKI definition.Kidney Int Suppl. 2012; 2: 19-36Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarStageSerum creatinineUrine output11.5–1.9 times baselineor≥0.3 mg/dl (≥26.5 mmol/l) increase<0.5 ml/kg/h for 6–12 h22.0–2.9 times baseline<0.5 ml/kg/h for ≥12 h33.0 times baselineorIncrease in serum creatinine level to ≥4.0 mg/dl (≥353.6 mmol/l)orInitiation of renal replacement therapyorIn patients younger than 18 yr, decrease in eGFR to <35 ml/min per 1.73 m2<0.3 ml/kg/h for 24 horAnuria for ≥12 hAKI, acute kidney injury; eGFR, estimated glomerular filtration rate. Open table in a new tab Table 2Risk factors for AKIModified from Kidney Int Suppl.1Section 2: AKI definition.Kidney Int Suppl. 2012; 2: 19-36Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarExposureSusceptibilitySepsisVolume deficiencyCardiac surgery and major noncardiac surgeryAgeCirculatory shockFemale sexCritical illnessChronic kidney diseaseBurnsChronic diseases (heart, liver, and lung)Major traumaDiabetes mellitusNephrotoxic drugs (e.g., aminoglycosides)CancerRadiocontrast agentsGenetic factorsAKI, acute kidney injury. Open table in a new tab AKI, acute kidney injury; eGFR, estimated glomerular filtration rate. AKI, acute kidney injury. A multitude of factors are involved in the pathophysiology of AKI. These can occur simultaneously or sequentially and include dysfunction of the endothelial barrier, disturbance of the macrocirculation and more importantly the microcirculation, injury of tubular cells, and inflammation of renal parenchyma. In clinical practice, the standard of estimating renal function is the determination of creatinine and urea levels and the balancing of diuresis. Nevertheless, it has been shown that creatinine and urea levels are insufficient and delayed markers in the diagnosis of AKI.7Barrett S.P. Salzman J. Circular RNAs: analysis, expression and potential functions.Development. 2016; 143: 1838-1847Crossref PubMed Scopus (68) Google Scholar Diuresis is influenced (independently of renal function) by a multitude of factors such as volume deficiency or diuretics. As these markers and urine output are insufficient in predicting AKI, many efforts have been made in establishing new and more sensitive biomarkers. Several molecules that are used to complement creatinine for an earlier and more sensitive detection include the following:•The cysteine protease inhibitor cystatin C, which is expressed ubiquitously,•Neutrophil gelatinase–associated lipocalin, a protein of the innate immune system,•Kidney injury molecule-1, which is synthesized by proximal tubular cells during AKI, and•Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinase 2, which are involved in the transition into G1 arrest of renal tubular cells. The areas under the curve in the context of AKI of these markers are 0.71 for cystatin C,8Koyner J.L. Bennett M.R. Worcester E.M. et al.Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery.Kidney Int. 2008; 74: 1059-1069Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar 0.67 for neutrophil gelatinase-associated lipocalin,9Han W.K. Wagener G. Zhu Y. et al.Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery.Clin J Am Soc Nephrol. 2009; 4: 873-882Crossref PubMed Scopus (235) Google Scholar 0.65 for kidney injury molecule-1,9Han W.K. Wagener G. Zhu Y. et al.Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery.Clin J Am Soc Nephrol. 2009; 4: 873-882Crossref PubMed Scopus (235) Google Scholar and 0.8 for the product of insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinase 2.10Kashani K. Al-Khafaji A. Ardiles T. et al.Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.Crit Care. 2013; 17: R25Crossref PubMed Scopus (325) Google Scholar The diagnostic value of the cell cycle arrest markers tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 was shown in the SAPPHIRE Study, where it was the best marker in predicting AKI stage 2 or 3.10Kashani K. Al-Khafaji A. Ardiles T. et al.Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.Crit Care. 2013; 17: R25Crossref PubMed Scopus (325) Google Scholar Its levels can be analyzed in the urine of patients at risk of AKI, e.g., in septic patients or in patients after cardiac surgery.11Schrezenmeier E.V. Barasch J. Budde K. et al.Biomarkers in acute kidney injury—pathophysiological basis and clinical performance.Acta Physiol (Oxf). 2017; 219: 554-572Crossref PubMed Scopus (30) Google Scholar As it can be measured by a fast and simple bedside test, it can be easily used in clinical practice. This can lead to an early identification of patients at risk of AKI. That may be beneficial for patients as it has been shown in the PrevAKI Study that early identification of patients at risk and early preventive strategies can reduce the rate of AKI.12Meersch M. Schmidt C. Hoffmeier A. et al.Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial.Intensive Care Med. 2017; 43: 1551-1561Crossref PubMed Scopus (52) Google Scholar As the therapeutic options in the treatment of AKI are limited to renal replacement therapy, it is of high importance to focus on the prevention of AKI. In the 2012 KDIGO guidelines, it is recommended to implement supportive measures in patients at high risk of AKI. These include routine measurements of creatinine levels and urine output, optimizing hemodynamics and volume status, avoidance or discontinuation of nephrotoxic substances, normoglycemia, and the use of alternatives to radiocontrast agents, if possible.13Section 3: Prevention and treatment of AKI.Kidney Int Suppl. 2012; 2: 37-68Abstract Full Text Full Text PDF PubMed Google Scholar Still nowadays, morbidity and mortality of patients suffering from AKI are high. Furthermore, there is a high clinical need to establish earlier and more precise diagnostic and therapeutic tools. To improve the precision of AKI diagnosis and uncover novel treatment targets, noncoding RNAs (ncRNAs) have come into focus of researchers as they might have a potential in the diagnosis as well as the treatment of AKI. Completion of the sequencing of the human genome in 200114Lander E.S. Linton L.M. Birren B. et al.Initial sequencing and analysis of the human genome.Nature. 2001; 409: 860-921Crossref PubMed Scopus (14420) Google Scholar, 15Venter J.C. Adams M.D. Myers E.W. et al.The sequence of the human genome.Science. 2001; 291: 1304-1351Crossref PubMed Scopus (9020) Google Scholar marked the beginning of extensive work aiming at characterizing the function of human genes. Although it was initially thought that the human genome was mostly composed of protein-coding genes, the revelation that only a small proportion of human genes were indeed able to encode proteins (∼2%) has been a major breakthrough in the characterization of the human genome16ENCODE Project ConsortiumAn integrated encyclopedia of DNA elements in the human genome.Nature. 2012; 489: 57-74Crossref PubMed Scopus (5964) Google Scholar (Figure 1). However, 80% of our genes are transcribed and lead to the synthesis of RNA molecules. These findings by the ENCODE Project Consortium16ENCODE Project ConsortiumAn integrated encyclopedia of DNA elements in the human genome.Nature. 2012; 489: 57-74Crossref PubMed Scopus (5964) Google Scholar implied that the majority of human genes are transcribed into non–protein-coding RNAs or more simply ncRNAs. The ncRNA family is a large and diverse class of RNAs with multiple functions. A simple classification of these RNA molecules relies on their size. An arbitrary cutoff of 200 nucleotides separates small ncRNAs from long ncRNAs (lncRNAs). The most widely investigated small ncRNAs are certainly microRNAs (miRNAs), which are 20- to 22-nucleotide-long RNA molecules and able to downregulate the expression of target protein-coding genes. miRNAs have been proposed as both disease biomarkers and therapeutic targets for personalized medicine.17Goretti E. Wagner D.R. Devaux Y. miRNAs as biomarkers of myocardial infarction: a step forward towards personalized medicine?.Trends Mol Med. 2014; 20: 716-725Abstract Full Text Full Text PDF PubMed Google Scholar The lncRNA group comprises both linear lncRNAs (named by default as lncRNAs) and circular RNAs (circRNAs). As miRNAs, lncRNAs, and circRNAs regulate gene expression and constitute a reservoir of potential novel disease markers and drug targets, the knowledge of the role of these 3 categories of ncRNA molecules (miRNAs, lncRNAs, and circRNAs) in kidney function and AKI are reviewed in the following sections. In 1993 lin-4, the first miRNA, was discovered in Caenorhabditis elegans.18Lee R.C. Feinbaum R.L. Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell. 1993; 75: 843-854Abstract Full Text PDF PubMed Scopus (6918) Google Scholar In the next 25 years, miRNAs have attracted attention in the context of various diseases including AKI. miRNAs are small ncRNAs that regulate gene expression posttranscriptionally.19Ambros V. microRNAs: tiny regulators with great potential.Cell. 2001; 107: 823-826Abstract Full Text Full Text PDF PubMed Scopus (998) Google Scholar In humans, >2000 mature miRNAs have been identified (miRBase, release 21; www.mirbase.org), thereby representing 1% of human genes.20Lim L.P. Glasner M.E. Yekta S. et al.Vertebrate microRNA genes.Science. 2003; 299: 1540Crossref PubMed Scopus (867) Google Scholar They are initially synthesized by RNA polymerase II, resulting in a precursor called pri-miRNA. The pri-miRNA is cleaved to a double-stranded pre-miRNA by the Drosha-DGCR8 complex.21Lee Y. Ahn C. Han J. et al.The nuclear RNase III Drosha initiates microRNA processing.Nature. 2003; 425: 415-419Crossref PubMed Scopus (3090) Google Scholar The pre-miRNA is exported from the nucleus into the cytoplasm via exportin 5 and further processed by the ribonuclease Dicer into small 20- to 23-nucleotide-long duplexes—the mature miRNA.22Ambros V. Bartel B. Bartel D.P. et al.A uniform system for microRNA annotation.RNA. 2003; 9: 277-279Crossref PubMed Scopus (1116) Google Scholar To exert its function, a single strand of the miRNA (in a majority of cases the guide strand) is incorporated into the RNA-induced silencing complex along with Argonaute and other proteins. The RNA-induced silencing complex targets the mRNA in the 3′-untranslated region, thus leading to the repression of protein translation or degradation of the mRNA.23Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (10324) Google Scholar There is evidence that miRNAs have a high potential in the diagnosis as well as in the treatment of various diseases. Their potential as diagnostic tools (biomarkers) is based on the fact that they are stable in fluids such as plasma24Gilad S. Meiri E. Yogev Y. et al.Serum microRNAs are promising novel biomarkers.PLoS One. 2008; 3: e3148Crossref PubMed Scopus (932) Google Scholar and easily detectable in comparison to plasma proteins. In contrast to other ncRNAs, some miRNAs show a tissue-enriched expression profile (e.g., miR-122 in the liver and miR-1 in the heart). Thus, they might represent a class of novel biomarkers in diseases such as myocardial infarction,17Goretti E. Wagner D.R. Devaux Y. miRNAs as biomarkers of myocardial infarction: a step forward towards personalized medicine?.Trends Mol Med. 2014; 20: 716-725Abstract Full Text Full Text PDF PubMed Google Scholar lung cancer,25Vencken S.F. Greene C.M. McKiernan P.J. Non-coding RNA as lung disease biomarkers.Thorax. 2015; 70: 501-503Crossref PubMed Scopus (21) Google Scholar or breast cancer.26Chan M. Liaw C.S. Ji S.M. et al.Identification of circulating microRNA signatures for breast cancer detection.Clin Cancer Res. 2013; 19: 4477-4487Crossref PubMed Scopus (126) Google Scholar A number of miRNAs (miR-21-5p, miR-20a-5p, miR-221, miR-223, and miR-145-5p), for example, has been shown to be dysregulated at early stages of non–small cell lung cancer,27Geng Q. Fan T. Zhang B. et al.Five microRNAs in plasma as novel biomarkers for screening of early-stage non-small cell lung cancer.Respir Res. 2014; 15: 149Crossref PubMed Google Scholar thus showing their potential in the early diagnosis of disease. As miRNA function can be regulated by specific antagonists or mimics, they are also promising future tools for the treatment of various diseases including AKI. Unlike miRNAs, which have been extensively studied over the past 5 years,28Lorenzen J.M. Haller H. Thum T. MicroRNAs as mediators and therapeutic targets in chronic kidney disease.Nat Rev Nephrol. 2011; 7: 286-294Crossref PubMed Scopus (127) Google Scholar only little information is available on the functional importance of lncRNAs. It is becoming evident that lncRNAs are important epigenetic regulators of tissue homeostasis during development and disease.29Lorenzen J.M. Thum T. Long noncoding RNAs in kidney and cardiovascular diseases.Nat Rev Nephrol. 2016; 12: 360-373Crossref PubMed Scopus (148) Google Scholar, 30Devaux Y. Zangrando J. Schroen B. et al.Long noncoding RNAs in cardiac development and ageing.Nat Rev Cardiol. 2015; 12: 415-425Crossref PubMed Google Scholar lncRNAs are novel regulatory RNA species, which may function as master regulators, modifying the expression of mRNAs and miRNAs and altering the chromatin architecture. Nuclear-enriched lncRNAs may regulate the chromatin architecture of genes on the same chromosome (in cis) or on another chromosome (in trans) by association with chromatin remodeling complexes.29Lorenzen J.M. Thum T. Long noncoding RNAs in kidney and cardiovascular diseases.Nat Rev Nephrol. 2016; 12: 360-373Crossref PubMed Scopus (148) Google Scholar Cytoplasmic lncRNAs may regulate the expression and function of miRNAs by interaction through miRNA response elements, thereby functioning as so-called miRNA sponges.29Lorenzen J.M. Thum T. Long noncoding RNAs in kidney and cardiovascular diseases.Nat Rev Nephrol. 2016; 12: 360-373Crossref PubMed Scopus (148) Google Scholar In addition, target mRNAs may be recognized and regulated.29Lorenzen J.M. Thum T. Long noncoding RNAs in kidney and cardiovascular diseases.Nat Rev Nephrol. 2016; 12: 360-373Crossref PubMed Scopus (148) Google Scholar Because of the lack of functional annotation for the majority of lncRNAs, different categories have been implemented on the basis of location with respect to protein-coding genes. lncRNAs may therefore be categorized as follows: (i) sense or (ii) antisense, (iii) bidirectional promoter (transcribed within 1 kb of promoters antisense to the protein-coding transcript), (iv) intronic, (v) intergenic, or (vi) enhancer-associated (transcribed from an enhancer region of a protein-coding gene)29Lorenzen J.M. Thum T. Long noncoding RNAs in kidney and cardiovascular diseases.Nat Rev Nephrol. 2016; 12: 360-373Crossref PubMed Scopus (148) Google Scholar (Figure 2). Although the function of most lncRNAs is unexplored to date, a mechanistic annotation has been suggested.31Wang K.C. Chang H.Y. Molecular mechanisms of long noncoding RNAs.Mol Cell. 2011; 43: 904-914Abstract Full Text Full Text PDF PubMed Scopus (1437) Google Scholar Here, lncRNAs were described to function as (i) signal lncRNAs, which are spatiotemporally transcribed in response to developmental cues, cellular context, or diverse stimuli; (ii) decoy lncRNAs, which affect transcriptional regulation by titrating transcription factors and other proteins away from chromatin; (iii) guide lncRNAs, which sequester ribonucleoprotein complexes and direct them to chromatin and other specific targets; or (iv) scaffold lncRNAs, which interact with multiple partners to form a chromatin-modifying complex (Figure 3). Very few lncRNAs have thus far been functionally characterized. For instance, lncRNAs play a critical role in the regulation of imprinting, exemplified by the long intergenic ncRNA Air and X-chromosome inactivation by Xist (X-inactive specific transcript).32Lorenzen J.M. Martino F. Thum T. Epigenetic modifications in cardiovascular disease.Basic Res Cardiol. 2012; 107: 245Crossref PubMed Scopus (69) Google Scholar The lncRNA H19 is imprinted with maternal expression.33Bartolomei M.S. Genomic imprinting: employing and avoiding epigenetic processes.Genes Dev. 2009; 23: 2124-2133Crossref PubMed Scopus (143) Google Scholar It has been shown to have a tumor-suppressive effect both in vitro and in vivo.34Hao Y. Crenshaw T. Moulton T. et al.Tumour-suppressor activity of H19 RNA.Nature. 1993; 365: 764-767Crossref PubMed Scopus (500) Google Scholar lncRNAs may therefore affect various diseases, including AKI, by distinct mechanisms involving all components of the cellular machinery.Figure 3Mechanistic classification of long noncoding RNAs (lncRNAs) (see text). (a) Signal lncRNAs are spatiotemporally transcribed and expressed to respond to developmental hints, cellular context, or diverse stimuli. Kcnq1ot1 recruits the histone 3 lysine 9 methylation (H3K9)– and histone 3 lysine 27 methylation (H3K27)–specific histone methyltransferases G9a and the polycomb repressive complex 2 (PRC2). (b) Decoy lncRNAs regulate transcription by titrating transcription factors and other proteins away from chromatin without exerting any additional functions. MALAT1 binds splicing factors regulating alternative splicing. (c) Guide lncRNAs bind ribonucleoprotein complexes, which are localized to chromatin and other specific targets. FENDRR interacts with PRC2 and thus induces H3K27. (d) Scaffold lncRNAs interact with multiple interaction partners, thereby leading to either transcriptional repression or activation. ANRIL binds polycomb repressive complex 1 (PRC1) and PRC2 and induces H3K27.View Large Image Figure ViewerDownload Hi-res image Download (PPT) circRNAs are relatively abundant and can be the predominant transcribed products for hundreds of genes.7Barrett S.P. Salzman J. Circular RNAs: analysis, expression and potential functions.Development. 2016; 143: 1838-1847Crossref PubMed Scopus (68) Google Scholar According to the last update of the most widely used database for circRNAs (circBase; http://www.circbase.org/35Glazar P. Papavasileiou P. Rajewsky N. circBase: a database for circular RNAs.RNA. 2014; 20: 1666-1670Crossref PubMed Scopus (215) Google Scholar), 92,000 circRNAs would exist, although several share similar sequences with only 1 or 2 different nucleotides. Several algorithms for the prediction of circRNAs from RNA sequencing data sets as well as several databases linking circRNAs to potential biological functions have been implemented and represent useful tools for the research on circRNAs. Interestingly, circRNAs are conserved in eukaryotes and have been detected in different cell types, developmental stages, and diseases. In addition, their expression can be highly cell type or tissue specific and is regulated upon disease progression. The biogenesis of circRNAs involves a back-splicing event between exons or introns within pre-mRNAs, leading to an association between an exon and an upstream exon or intron.36Jeck W.R. Sharpless N.E. Detecting and characterizing circular RNAs.Nat Biotechnol. 2014; 32: 453-461Crossref PubMed Scopus (395) Google Scholar In the canonical splicing process forming mRNAs, an exon is associated with an adjacent downstream exon. The back-splicing event leads to circRNAs that contain a few exons or introns.37Ashwal-Fluss R. Meyer M. Pamudurti N.R. et al.circRNA biogenesis competes with pre-mRNA splicing.Mol Cell. 2014; 56: 55-66Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar, 38Starke S. Jost I. Rossbach O. et al.Exon circularization requires canonical splice signals.Cell Rep. 2015; 10: 103-111Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar RNA binding proteins such as Muscleblind,37Ashwal-Fluss R. Meyer M. Pamudurti N.R. et al.circRNA biogenesis competes with pre-mRNA splicing.Mol Cell. 2014; 56: 55-66Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar Quaking,39Conn S.J. Pillman K.A. Toubia J. et al.The RNA binding protein quaking regulates formation of circRNAs.Cell. 2015; 160: 1125-1134Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar or RNA binding motif protein 2040Khan M.A. Reckman Y.J. Aufiero S. et al.RBM20 regulates circular RNA production from the titin gene.Circ Res. 2016; 119: 996-1003Crossref PubMed Scopus (46) Google Scholar also contribute to the biogenesis of circRNAs. Conversely, the RNA-editing enzyme adenosine deaminase, RNA specific (ADAR1) antagonizes the production of circRNAs.41Ivanov A. Memczak S. Wyler E. et al.Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals.Cell Rep. 2015; 10: 170-177Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 42Rybak-Wolf A. Stottmeister C. Glazar P. et al.Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed.Mol Cell. 2015; 58: 870-885Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar For more mechanistic details of the formation of circRNAs, see Figure 4 and recent reviews.43Devaux Y. Creemers E.E. Boon R.A. et al.Circular RNAs in heart failure.Eur J Heart Fail. 2017; 19: 701-709Crossref PubMed Scopus (16) Google Scholar, 44Chen L.L. The biogenesis and emerging roles of circular RNAs.Nat Rev Mol Cell Biol. 2016; 17: 205-211Crossref PubMed Scopus (176) Google Scholar As other ncRNAs, circRNAs have the ability to regulate gene expression through different mechanisms (Figure 4). They can act as a sponge for miRNAs, thereby preventing their repression of target genes and acting as gene expression enhancers. In contrast, circRNAs can be degraded through the binding of miRNAs. In addition, circRNAs can act as scaffolds for transcription factors, retaining them in the cytoplasm or shuttling them to target locations in the genome. Synthesis of circRNAs by back-splicing of a precursor RNA can lead to a decreased expression of the linear form of the hosting gene. It has to be noted that although the consensus tends to be an absence of protein-coding potential for most circRNAs, and hence their classification as ncRNA molecules, recent studies support the ability of some circRNAs to encode proteins.45Pamudurti N.R. Bartok O. Jens M. et al.Translation of circRNAs.Mol Cell. 2017; 66: 9-21.e27Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 46Legnini I. Di Timoteo G. Rossi F. et al.Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis.Mol Cell. 2017; 66: 22-37.e29Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar The first miRNA targeting molecule that entered clinical trials is the inhibitor of miR-122, a liver-specific miRNA. The miR-122 inhibitor is tested clinically in patients suffering from hepatitis C virus infections. To date, miRNA inhibitors or mimics addressing the treatment of AKI have not been introduced. The first study addressing an effect of miRNAs on the pathogenesis of AKI was published in 2010. Using a Dicer knockout mouse model with specific deletion of Dicer in renal proximal tubular cells, Wei and colleagues showed that these knockout mice had better renal function and less tissue damage after bilateral ischemia-reperfusion (I/R) injury of kidneys.47Wei Q. Bhatt K. He H.Z. et al.Targeted deletion of Dicer from proximal tubules protects against renal ischemia-reperfusion injury.J Am Soc Nephrol. 2010; 21: 756-761Crossref PubMed Scopus (129) Google Scholar In various animal models of AKI, a significant up- and downregulation of miRNAs has been shown (summarized in Table 3). In a bilateral renal ischemia mouse model, Bellinger and colleagues demonstrated that a number of miRNAs are differentially expressed in the kidney and plasm" @default.
• W2896724865 created "2018-10-26" @default.
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• W2896724865 date "2018-11-01" @default.
• W2896724865 modified "2023-10-10" @default.
• W2896724865 title "Noncoding RNAs in acute kidney injury" @default.
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