[雙語翻譯]--醫(yī)學(xué)外文翻譯--microrna在腎臟疾病中的作用（英文）

1、Review ArticleReview: The role of microRNAs in kidney diseasenep_1363 599..608JORDAN YZ LI,1,2 TUCK Y YONG,2,3 MICHAEL Z MICHAEL2,4 and JONATHAN M GLEADLE1,2Departments of 1Renal Medicine and 3General Medicine and 4Gastr

2、oenterology and Hepatology, Flinders Medical Centre, and 2School of Medicine, FlindersUniversity, Adelaide, South Australia, Australia.KEY WORDS:biomarker, diabetic nephropathy,epithelial-mesenchymal transition, kidneydi

3、sease, microRNA.Correspondence:Professor Jonathan Gleadle, Department ofRenal Medicine, Level 6, Flinders MedicalCentre, Flinders Drive, Bedford Park, SA 5042,Australia. Email: jonathan.gleadle@health.sa.gov.auAccepted f

4、or publication 30 May 2010.Accepted manuscript online 7 June 2010.doi:10.1111/j.1440-1797.2010.01363.xSUMMARY AT A GLANCEThis is a comprehensive and scholarlyreview of the current knowledge ofmicroRNAs (miRNAs) in renal

5、disease.MiRNAs are emerging as importantregulators of disease processes.Understanding how miRNAs modulatepathogenetic pathways is important, astherapeutic manipulation of miRNAs mayevolve as a potential strategy for trea

6、tingrenal diseases in the future.ABSTRACT:MicroRNAs (miRNAs) are short non-coding RNAs that modulate physi-ological and pathological processes by inhibiting target gene expression viablockade of protein translation or by

7、 inducing mRNA degradation. ThesemiRNAs potentially regulate the expression of thousands of proteins. As aresult, miRNAs have emerged rapidly as a major new area of biomedicalresearch with relevance to kidney disease. Mi

8、RNA expression has beenshown to differ between the kidney and other organs as well as betweendifferent kidney regions. Furthermore, miRNAs have been found to befunctionally important in models of podocyte development, di

9、abetic neph-ropathy and polycystic kidney disease. Of particular interest, podocyte-specific deletion of Dicer, a key enzyme in the biogenesis of miRNA, resultsin proteinuria and severe renal impairment in mice. One miRN

10、A (miR-192)can also act as an effector of transforming growth factor-b activity in thehigh-glucose environment of diabetic nephropathy. Differential expressionof miRNAs has been reported in kidney allograft rejection. It

11、 is anticipatedthat future studies involving miRNAs will generate new insights into thecomplex pathophysiology underlying various kidney diseases, generatediagnostic biomarkers and might be of value as therapeutic target

12、s forprogressive kidney diseases. The purpose of this review is to highlight keymiRNA developments in kidney diseases and how this might influence thediagnosis and management of patients with kidney disease in the future

13、.INTRODUCTIONMicroRNAs (miRNAs) are endogenous non-coding RNA mol-ecules, 20–22 nucleotides in length. The discovery and char-acterization of miRNA in the last decade is revolutionizing ourunderstanding of gene regulatio

14、n, cell differentiation, prolif-eration, apoptosis, metabolism and pathophysiology of manydiseases including kidney diseases. The understanding ofmiRNA biology and its role in various diseases is still in itsearly stage

15、but is expanding rapidly. The aim of this review isto highlight miRNA biology in relation to kidney diseases andits importance in understanding disease mechanisms. Futuredirections in this field will also be discussed.DI

16、SCOVERY AND BIOGENESIS OF MICRORNAsMiRNAs were first found in the nematode Caenorhabditiselegans in 1993.1 Since then they have also been describedwidely in plants and mammals.2 MiRNAs are first transcribedin the nucleus

17、 as stem-loop primary miRNA, which are thencleaved into shorter precursor miRNA by Drosha, an RNaseIII, and its essential cofactor called DGCR8 (DiGeorge syn-drome critical region 8), a double-stranded RNA-bindingprotein

18、 (Fig. 1).3–6 The precursor miRNAs are transported outof the nucleus via Exportin-5 and once in the cytosol arecleaved into their mature form of 20–22 nucleotides by Dicer,another RNase III.7,8 After cleavage, the miRNA

19、duplex isunwound and the functional strand is loaded onto the RNA-induced silencing complex (RISC) and functions as its guide.9The mature miRNA guides the RISC complex to a (near)complementary sequence, usually in the 3′

20、 untranslatedregion (UTR), of a target messenger RNA (mRNA).9 Uponbinding, the RISC causes post-transcriptional gene silencingby either cleaving the target mRNA or by inhibiting its trans-lation, so that miRNAs are usual

21、ly negative regulators ofgene expression.10 In addition to their role in such post-transcriptional repression, miRNAs have now been implicatedNephrology 15 (2010) 599–608© 2010 The AuthorsNephrology © 2010 Asia

22、n Pacific Society of Nephrology 599enable monitoring in a clinical setting. Originally, RNA blotanalyses provided both quantitative and qualitative informa-tion about the various forms of a miRNA within a total RNAsample

23、.1,16 As the number of miRNAs in the miRBase regis-try17 has increased, microarray technology has been adaptedto enable the parallel screening of thousands of miRNAs inone sample.18 More recently, real time reverse trans

24、cription-polymerase chain reaction has been adapted to enable rela-tive quantification and quantitative analysis of miRNA levels.Specific amplification of mature miRNAs can be achievedusing stem-loop oligonucleotides to

25、prime reverse transcrip-tion and enable TaqMan detection,19 while alternate reagentsand methods for amplifying precursor and primary tran-scripts are also commercially available. Microfluidic systemsnow enable high throu

26、ghput miRNA PCR profiling withsmall amounts of input sample RNA, enabling analysis ofsmall biopsies, limited volumes of body fluids, or evenformalin-fixed paraffin-embedded archival material.20 Thehybridization kinetics

27、of oligonucleotides have beenenhanced through the incorporation of locked nucleic acidmonomers, which provide an advantage for PCR and in situhybridization21 and also enhance the potential for employinganti-miRNA strateg

28、ies in therapeutic roles.22,23MICRORNAS IN RENAL PHYSIOLOGYThe suggestion of organ-specific roles for miRNAs emergedwith the demonstration of tissue-restricted miRNA expres-sion, including clusters of miRNAs that are exp

29、ressed specifi-cally in the kidney.24 Conversely, the absence or lower levelsof particular miRNAs in the kidney compared with otherorgans may permit renal specific expression of target proteinsthat are important for kidn

30、ey function.24,25 Examples ofmiRNAs that are more abundant in the kidney comparedwith other organs include miR-192, miR-194, miR-204,miR-215 and miR-216. Tian et al. established the first differ-ential profile of miRNA e

31、xpression between the renal cortexand medulla of rats indicating a potential role in tissue speci-fication.26 However, cell type-specific miRNAs in the kidneyhave not yet been reported.A critical role of miRNA regulation

32、 in the progression ofglomerular and tubular damage, and the development ofproteinuria have been suggested by studies in mice withpodocyte-specific deletion of Dicer.27–29 All three reportsshowed major renal abnormalitie

33、s in these mice includingproteinuria, podocyte foot process effacement, glomerularbasement membrane abnormalities, podocyte apoptosis,podocyte depletion and mesangial expansion. There was arapid progression of renal dise

34、ase with initial development ofalbuminuria followed by pathological features of glomerulo-sclerosis and tubulointerstitial fibrosis. This led to renal failureand death by 6–8 weeks. It is likely that these phenotypes are

35、due to the global loss of miRNAs because of Dicer deletion, butgiven multiple miRNAs and their myriad targets, the precisepathways responsible require identification.These investigators also identified specific miRNA cha

36、nges,for example, the downregulation of the miR-30 family whenDicer was deleted. Of relevance, the miR-30 family wasfound to target connective tissue growth factor, a profibroticmolecule that is also downstream of transf

37、orming growthfactor (TGF)-b.30 Thus, the targets of these miRNAs mayregulate critical glomerular and podocyte functions. Thesefindings have also been complemented by an elegant studyrevealing a developmental role for the

38、 miR-30 family duringpronephric kidney development in Xenopus.31Recently, another study has shown that deletion of Dicerin the renin secreting cells of mice severely reduced thenumber of juxtaglomerular cells, decreased

39、expression of therenin genes, lowered plasma renin concentration anddecreased blood pressure.32 The kidneys developed strikingvascular abnormalities and prominent striped fibrosis. Thesefindings highlight the important r

40、oles of Dicer and miRNAsin renal physiology and pathology, although the extent towhich such genetic studies reveal an essential and funda-mental role of Dicer in cellular function, as opposed to aspecific role in renin s

41、ecreting cells, is arguable. The impor-tance of Dicer in cellular function is further highlighted byWei’s study.33 They established a mouse model with targetedDicer deletion in renal proximal tubules. These mice hadnorma

42、l renal function and histology despite a global down-regulation of miRNAs in the renal cortex. However, thesemice were strikingly resistant to renal ischaemia-reperfusioninjury, showing significantly better renal functio

43、n, less tissuedamage, lower tubular apoptosis and improved survivalcompared with their wild-type counterparts.33MICRORNAS IN RENAL DISEASESDiabetic nephropathyDiabetic nephropathy is the leading cause of end-stagekidney

44、disease but our understanding of the disease mecha-nisms is incomplete. Studies of miRNA expression in diabeticnephropathy have so far emerged predominantly fromanimal models of diabetes and the effects of hyperglycaemia

45、.In one study, miR-192 levels were shown to be increased inglomeruli isolated from streptozotocin-injected diabetic miceand diabetic mice db/db when compared with non-diabeticmice.34 In this study, miR-192 was shown to r

46、egulate E-boxrepressors that are responsible for controlling the expressionof TGF-b-induced extracellular matrix proteins, collagen 1-a1 and 2 (Col1a1 and 2). Col1a1 and 2 were shown to accu-mulate during diabetic nephro

47、pathy; therefore, these resultssuggest a potential role of miR-192 in diabetic nephropathyor that miR-192 can be an effector of TGF-b. However, dis-cordantly a recent study demonstrated that miR-192 expres-sion is decrea

48、sed in proximal tubular epithelial cells inresponse to TGF-b.35 The loss of miR-192 correlates withtubulointerstitial fibrosis and reduction in eGFR in renalbiopsies from patients with established diabetic nephropathy.Mi