Kidney transplantation is the treatment of choice for patients with end-stage kidney diseases (ESKD) that increases patients’ survival and improve quality of life (1,2). During the past decades by introduction of new and potent immunosuppressive drugs and improvements in surgical techniques, the incidence of acute rejection (AR) has decreased from 50% to about 10%. Early detection of AR and early initiation of proper anti-rejection therapy remains as a frequent and serious challenge in preventing allograft damage or loss (3-5). Currently, acute allograft rejection is diagnosed by rising serum creatinine level or by performing multiple and repeated kidney allograft biopsies. Allograft biopsy is invasive, costly and may be associated with poor interpretation, sampling error or even very rarely with graft loss (6-8). Unfortunately, rise in serum creatinine level or histological abnormalities in biopsy is seen when approximately 40–50% of reversible or irreversible graft parenchyma damage has been already occurred (9,10). The etiology of AR is related to the infiltrating cells of the recipient’s immune system that affects kidney hemodynamics and molecular regulatory factors and in turn leads to T-cell mediated or adaptive antibody-mediated graft rejection (11-13).
By understanding of non-coding RNAs’ (ncRNAs) function, cellular biology has revolutionized and a totally novel level of gene transcription regulation mechanism has been introduced which gain the attention of research groups to explore different expression patterns of ncRNAs in the field of organ transplantation (14,15). To date myriad efforts have been done to find out more about molecular mechanisms underlying AR to identify patients at high risk and early detection of affected patients (16,17). It is evident that the pathologic processes at molecular level occur long before histological abnormalities and clinical manifestations. Unfortunately we are still far away from understanding ncRNAs’ related molecular signaling networks which occur in AR.
Molecular mechanisms of AR at a glance
Innate and adaptive immune systems both play key roles in rejection mechanism. Being a result of genetic differences between organ donor and recipient, transplanted graft consists of many foreign antigens that can trigger the recipient’s immune response and lead to activation of T and B cells of recipient’s adaptive immune system following recognition of non-self antigens (alloimmune response) (18). Allorecognition mainly depends on the cell-surface proteins called major histocompatibility complex (MHC) molecules. There are two classes of MHCs: class I, that are constitutively expressed on all nucleated cells; and class II, that are constitutively expressed only on antigen presenting cells (APCs) such as dendritic cells (DCs), macrophages (MQs) and the B cells. After vascularization of a transplanted organ, depending on the source of the APCs, recipient’s T cells recognize donor-derived antigens through two distinct pathways: direct pathway, in which intact non-self MHC molecules on the surface of donor cells is recognized and a potent anti-graft immune response is elicited; and indirect pathway, in which donor fragmented MHC molecules on the surface of recipient’s MHC molecules is recognized that induce a less intense immune response (18,19). In direct pathway, CD8 positive cytotoxic T cells recognize peptides within class I MHC molecules while CD4 positive helper T cells recognize peptides within class II MHC molecules. It is believed that alloreactive T cells have the ability to recognize polymorphic residues on allogenic MHC regardless of processed peptide bound to it (20). After T cell receptor CD3 (TCR-CD3) associated allorecognition-specific signal (signal 1) and accessory (CD4 or CD8) and costimulatory (ex: CD40/CD40L or CD28/B7 pathway) signal (signal 2), a chain of signaling protein phosphorylation is induced for genes transcription and T cells become activated (18,19,21-23). Tissue destruction happens following T cell mediated lysis of graft cells, activation of accessory T cells and their byproducts such as granzyme B and perforin, B cells mediated anti-transplant antibody production, cytokines production and complement activation (18,19,24,25). Regulatory T cells (Treg) can suppress immune responses through suppressor cytokines production, modulating of DCs’ maturation/function and suppression of effector cells; such as MQs and natural killer (NK) cells (18,19,26-28) providing tolerance and graft survival in transplant recipients. Activated T and B cells also can differentiate into memory cells that can respond more quickly and strongly to an antigen years after its first presentation (19).
Definition of ncRNAs
In humans, genome consists of the intron sequences, 3’ or 5’ untranslated regions, the protein—coding sequences (~28%) and other transcripts that are referred to as ncRNAs (29). Since they play important roles in regulatory pathways engaged in biological functions and human diseases, in recent years this field has gained international attention by investigators as a new discipline in biological research. However except for miRNAs, still intense efforts are needed to focus on elucidating detailed function and mechanisms of action underlying other types of ncRNAs. Non-coding RNAs are divided into three groups according their length: (I) small ncRNAs such as: endogenous small interfering RNAs (endo-siRNAs), microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), transcription initiation RNAs (tiRNAs); (II) mid-size ncRNAs such as: transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs); and (III) long ncRNAs such as: XIST, HOTAIR, AIR, very long intergenic RNAs (vlincRNAs), macro lncRNAs. Many of ncRNAs may fall into more than one group such as: promoter associated RNAs (PATs), enhancer associated RNAs (eRNAs) and circular RNAs (circRNAs) (30-34). Part of currently identified nc-RNAs and their characteristics are highlighted in (Table 1). Some other nc-RNAs which are not described in H. sapiens are not mentioned here.
MiRNAs, lncRNAs and circRNAs have been detected in tissue samples and easily accessible body fluids such as peripheral blood mononuclear cells (PBMCs), serum, plasma, urine cell pellets and urine supernatant (58-62). They even are found in packed forms into macrovesicles, exosomes or HDL and can be picked up by neighboring cells functioning as secondary messenger molecules and growing evidence shows that their dysregulation is implicated in kidney diseases and AR (63-67). Taking the aforementioned kidney biopsy substantial risks and the existence of an urgent need to discover early noninvasive biomarkers, ncRNAs seems to be as promising candidates to tackle these problems by better stratification of rejection risks, diagnosis, monitoring the progression of AR and evaluation of treatment strategies which in turn may lead to improvement in allograft survival and patient outcome.
Biogenesis and function of MicroRNA
MicroRNAs (miRNAs) are short (~22 nt in length) single stranded endogenous non-coding RNAs that are able to regulate gene expression by repressing mRNA translation or enhancing of mRNA decay (68,69). Several studies has shown that miRNA play pivotal roles in wide range of biological processes, such as cell differentiation, organ development, apoptosis, innate and adaptive immunity, cell death, stress responses and diseases (70-74). MiRNAs exhibit temporal and tissue-specific expression patterns. The miRNA biogenesis starts from long primary transcripts of relative genes (pri-miRNA) generated from RNA polymerase II (RNA Pol II). Following cleavage by microprocessor complex DROSHA and Di-George syndrome critical region gene 8 (DGCR8), a stem-loop structural precursor (pre-miRNA) of about 70 nt long is generated and then exported to the cytoplasm by Exportine5 through the nuclear pores where they are further processed by the Dicer into ~22 nt duplexes of mature miRNAs. After unwinding of dsRNA and loading of guide-strand onto the RNA-Induced Silencing Complex (RISC), the final complex recognizes target mRNAs via complementary binding of seed sequences (6–8 nt) to them and in turn degrade them or inhibit their translations (75-77). Intriguing fact about microRNAs is that a single type miRNA is able to bind to many different mRNA targets and regulates their expression. On the other hand, a single mRNA can be targeted by variety of miRNAs (78,79). Some evidences showed that miRNAs can play roles as transcriptional activators or co-activators of several genes (80). It is believed that AR, as frequent complication of kidney transplant, is associated with alterations in interplay relationship between mRNAs and miRNAs that are highly regulated molecular mechanisms (81). Thank to solid base technologies studying and monitoring of antibody mediated immunity has been remarkably progressed, but T-cell mediated immunity is still mainly depends on invasive tissue biopsies (67,82,83).
Biogenesis and function of lncRNA
Noticeable portion of human genome is actively transcribed into lncRNAs that recently has been shown some of them harbor short open reading frames (sORF) which minority of them translated to stable and functional peptides with even enhancer role (84-87). Most of lncRNAs but not all of them resemble mRNAs with respect to synthesizing by RNA Pol II or rarely by RNA Pol III (88), 5’capped (except for the intronic RNAs and circRNAs) and 3’-end polyadenylated, non polyadenylated or as both forms (bimorphic transcripts) (89-92). Aside RNA Pol machinery, for their transcription, they need assisting factors such as pre-initiation complex, mediators, transcription elongation complex and transcription factors (93). Their promoters are more conserved than the promoter of protein coding genes (94) and enriched in A/T mono-, di- and trinucleotide stretches while the levels of histone H3K4 trimethylation (H3K4me3) are reduced in them leading lower transcription rate (95). Just like as protein coding genes, lncRNA genes comprise multi-exonic regions with identical splicing signals that leads to production of many different isoforms with specific functions (96-98).
lncRNAs may localize either in nucleus or in cytosol (99) but under special conditions such as environmental changes or infection they can be delocalized from one cellular compartment to another (100). Nuclear lncRNAs mainly are related to chromatin architecture of genes in cis or in trans (101) while cytoplasmic ones are believed to be competing endogenous RNAs that can regulate miRNAs (101). lncRNAs exhibit highly specific tissue- and cell-type expression patterns compared with protein coding genes (93,102). On the basis of their genomic location they are categorized into six following groups: (I) intergenic; (II) intronic; (III) bidirectional protein associated; (IV) sense; (V) antisense and (VI) enhancer associated (93,101,103).
Regarding the role of lncRNAs in gene expression regulation, they can be classified as: (I) scaffold lncRNAs that recruit multiple partners in order to form chromatin modifying complex (104); (II) guide lncRNAs that sequester ribonucleoprotein complexes and direct them to target genes (101,105); (III) elncRNs that are transcribed from enhancer elements and link the enhancer to the promoter to increase transcription (106,107); (IV) signal lncRNAs that are transcribed in response to different developmental and environmental stimuli (101,104); (V) decoy lncRNAs that can tittering away transcription factors, induce RNA degradation, functioning as sponges and tittering the miRNAs’ concentrations and compete with them for binding to target mRNA (108,109). Although in some cases it has been shown that lncRNAs-protein interactions are sequence independent and even exon deletions or sequence replacement does not affect neighboring genes’ expression (110-113), it has been demonstrated that some single nucleotide polymorphisms (SNPs) within lncRNAs or their promoters contribute to some disease- associated pathologies (114).
MicroRNAs in acute kidney transplant rejection
Increasing number of studies suggest that miRNAs have critical regulatory roles in innate and adaptive immune responses and thus in organ status after transplantation.
The relationship between hematopoietic cells’ differentiation stages and miRNA profiling status was first described by Monticelli et al. in the murine hematopoietic system in which increased levels of miR-142-3p in naïve T cells compared with differentiated Th1 and Th2 cells has been reported (115). According to genomic studies the molecular injury in chronic allograft nephropathy (CAN) and AR resembles. This likely reflects the threshold effect for AR at which the same molecular injuries occurs at higher and sever levels in AR compared with CAN (17). Surprisingly, increased levels of forkhead box protein 3 (FOXP3) transcription factor’s mRNA was observed in urine samples of patients with AR (90% sensitivity and 73% specificity) compared with patients with CAN and recipients with normal biopsy results (116). This finding was confirmed by other studies (117,118). FOXP3 is known as miR-142-3p transcription repression mediator and it is expected to decrease the expression level of it (119). Further studies revealed that normally the expression of two opposite arms of miR-142 in hematopoietic cell lineage are different and the expression level of miR-142-3p (3’ arm of miR-142) is approximately 10 times more than that of miR-142-5p (5’ arm of miR-142) (120). In 2011, performing an investigation of miRNA, mRNA and protein expression on activated T lymphocytes, Grigoryev et al. introduced the concept of miR-142-3p being associated with tolerant kidney allograft recipients while decreased levels of miR-155 and miR-221 are associated with T-cell proliferation (121). The results of subsequent studies revealed that miR-142-3p, miR-204 and miR-211 can be used to distinguish patients with CAN from those without (122-124). Also the overexpression of miR-142-3p in PBMCs of operationally tolerant kidney transplant recipients has been shown (125). Soltaninejad et al. identified 4 miRNAs (miR-142-3p, miR-142-5p, miR-155 and miR-223) that were abundantly expressed in 17 biopsy samples as well as two miRNAs (miR-142-3p and miR-223) in their paired PBMC samples of patients with confirmed TMAR compared with patients with stable graft function (SGF) (126). Previously Anglicheau et al. found that miR-142-5p, miR-155, and miR-223 that are highly expressed in AR biopsies are overexpressed in normal PBMCs too (127). Liu and Xu have found that miR-223 was increased 2 folds in PBMCs of patients with AR within 1 month after kidney transplantation (128).
A recent study conducted by Domenico et al., showed that miR-142-3p is significantly increases in peripheral blood and urine of kidney transplant recipients with acute tubular necrosis (ATN) but not in those with SGF and AR (129). The authors supported another study’s findings and suggested that this provide strong evidence for necrosis processes and inflammatory injuries such as interstitial fibrosis and tubular atrophy (IF/TA) (124,129). MiR-142-5p overexpression in non-invasive samples was found in patients with chronic antibody mediated rejection but not in those with AR or SGF (130).
In a study using sera from 42 kidney transplant recipients the association of circulating miR-21 levels with renal fibrosis severity was assessed. The fibrosis grades were evaluated by allograft biopsy result interpretations and authors concluded that levels of circulating miR-21 are significantly increased in cases with sever IF/TA but not in other renal histological lesions (131).
In one study the circulating miRNAs in urinary samples of patients with AR, patients before and after rejection, patients with urinary tract infection (UTI) and patients with SGF were performed. Deregulation of miR-10a, miR-10b and miR-210 in urine samples of patients with AR, from which miR-10b and miR-210 were down-regulated while miR-10a was up-regulated in Acute TCMR patients compared with those with SGF were determined. It was also shown that decreased levels of miR-210 were associated with higher glomerular filtration rate (GFR) during first year after transplantation. Among aforementioned deregulated miRNAs, it was determined that only expression level of miR-210 was corrected after successful rejection treatment (132). Conversely Betts et al. examined the sera of patients with AR and found that miR-223 and miR-10a to be significantly down-regulated during AR compared with patients with SGF and without a history of rejection (133). Liu et al. performed miRNA next generation sequencing in normal and acutely rejected kidney allografts. The main finding was that miR-10b was significantly down-regulated in AR inducing glomerular endothelial cell apoptosis by derepressing of its pro-apoptotic target, B-cell lymphoma2-like-11protein (BCL2L11), and releasing of pro-inflammatory cytokines and MQs chemotaxis. All of these are key features of AR and the authors suggested that restoring of miR-10b expression in glomerular endothelial cells can be used as therapeutic approach in order to ameliorate acute kidney allograft loss (134).
Lv et al. showed that miR-29-c in urinary exosomes correlated with GFR and could be used for distinguishing mild from moderate to severe fibrosis with 68.8% sensitivity and 81.3% specificity (135).
Sui et al. integrated array-based proteomics and microarray-based genomics data to find transcription factors (TF), miRNAs and ncRNAs of biopsy specimens from patients with AR in order to further understand the mechanism underlying AR. They reported the expression of 5 TFs (AP-1, AP-4, STATX, c-Myc and P53), 12 miRNAs and 32 ncRNAs with critical roles in molecular signaling pathways related to AR. For example, down-regulation of has-miR-324-3p and up-regulation of has-miR-381 had been correlated with poor prognosis or key proteins with regulatory effects on apoptosis, innate immunity, inflammation and hematopoietic differentiation are repressed by miR-125b at translation level (136). Also they investigated the expression levels of miR-181a, miR-483-5p and miR-557 in sera samples of 15 kidney transplant recipients before transplantation, on the first, third and seventh days after transplantation by RT-PCR. Based on receiver operating characteristic (ROC) analysis results, they concluded that these three miRNAs could serve as predictive biomarkers for rejection (137). This same research group in a study conducted in 2008, have indicated an AR profile of 20 miRNAs in biopsy samples of 3 patients with AR and compared them with 3 patients with SGF, out of which 2 (miR-320 and miR-324-3p) were confirmed by QRT-PCR (118).
A research group led by Wilflingseder, has also done a number of studies regarding miRNAs expression patterns according to rejection type or injury in renal transplantation. In 2013, they reported miRNA signatures that discriminate acute TCMR (up-regulation: miR-150, miR-155, miR-663 and miR-638; down-regulation: 18 miRNAs; miR-125b-2, miR-99b, miR-30-c-2 and miR-424), acute ABMR (up-regulation: miR-146-5p, miR-1228, let-7i, miR-21, miR-182, miR-155, miR-125a and miR-146b) and delayed graft function (DGF) (138). Following year, they showed a molecular acute kidney injury (AKI) signature consisting 20 mRNAs and 2 miRNAs (miR-182-5p and miR-21-3p) from which miR-182-5p was identified as biomarker in addressing AKI (139).
Tao et al., found 6 deregulated miRNAs in serum samples of patients with AR compared with kidney recipients with SGF and patients with DGF. Out of 6, up-regulation of only 2 (miR-99a and miR-100) were confirmed by QRT-PCR in AR patients and according to ROC analysis, only miR-99a had a potent diagnostic value for discriminating patients with AR from those with SGF or with DGF. Thus they concluded that serum level of miR-99a could serve as a biomarker for detection of AR (140).
Rejection associated events such as production of cytokines and growth factors can result in microvascular endothelial cells damage and promotion of dysregulated angiogenesis within the graft (141). Bijkerk et al. selected 48 miRNAs to assess the AR and microvascular injury associated circulating miRNAs in plasma samples of 13 patient with AR on the first, sixth and twelve months after AR and 25 transplant recipients with SGF using QRT-PCR. The investigators identified 8 miRNAs (up: miR-17, miR-140-3p, miR-130b, miR-122 and miR-192; down: miR-135a, miR-199a-3p, miR-15a) as being able to discriminate AR and SGF. Furthermore, the authors showed miR-130b, miR-199a and miR-192 were associated with markers of vascular injury. MiR-140-3p, miR-130b, miR-122 and miR-192 were normalized within 1 year after AR (142). Cheng et al. investigated the role of miRNA-181b in peripheral blood of renal allograft recipients whit acute vascular rejection (n=14) and non-acute vascular rejection (n=20) using QRT-PCR. They found that the expression level of peripheral blood miR-181b in patients with acute vascular rejection was remarkably lower at different time points of 1, 2, 3 and 4 weeks post transplantation compared with that of the non-acute vascular rejection. Furthermore the authors suggested that miR-181b might be one of the markers for monitoring of acute vascular rejection after kidney transplantation (143).
Recently in a study Matz et al. from France aimed to identify miRNAs signature in ABMR and IF/TA using high-throughput sequencing and validated results in 53 patients with SGF, 17 with UTI, 19 with borderline rejection (BL), 40 with TCMR, 22 with ABMR and 30 with IF/TA by QRT-PCR. miR-142, miR-223-3p, miR-424-3p and miR-145-5p could discriminate acute TCMR and acute ABMR only from SGF, but not from others. Also miR-145-5p was identified as IF/TA specific biomarker from SGF only and others combined with highly diagnostic accuracies (AUC =0.891 and AUC =0.835 respectively) (144).
Finally, Misra et al. from India investigated the impact of 4 SNPs namely MIR146A C>G (rs2910164), MIR149 T>C (rs2292832), MIR196A2 T>C (rs11614913), and MIR499A A>G (rs3746444) among patients with end-stage renal disease (ESRD) and those with AR. They observed an increased risk of approximately two-fold in ESRD and three-fold in AR for mutant genotypes of rs2910164, rs11614913, and rs3746444. They concluded that these SNPs might have roles in susceptibility to ESRD and AR (145).
lncRNAs in acute kidney transplant rejection
As mentioned before, since TFs, miRNAs and lncRNAs are the most important gene regulators, Sui et al. for the first time investigated and constructed the regulation network of the target genes by 5 TFs, 12 miRNAs and 32 lncRNAs which were differentially expressed in biopsy specimens from patients with AR integrating high throughput screening data and different algorithms’ data (136).
Using lncRNAs microarray Chen et al. studied the differentially expressed lncRNAs in biopsy tissue samples of 3 patients with AR and compared them with those with SGF. Then based on their expression fold changes five lncRNAs (uc001fty, uc003wbj, AK129917, uc010ftb and AF113674) have been chosen to be validated by QRT-PCR (146). Taking the notion that depending on their genomic location lncRNAs have divers regulatory functions such as negatively/positively regulating the target gene, protein-coding mRNA stabilization, regulation of alternative splicing of mRNAs and etc. (147); they have done KEGG pathway enrichment analysis for these five lncRNAs to gain new insights into the pathogenesis of AR. The authors concluded that AR is associated with immune activation and inflammation (146).
Lorenzen et al. analyzed the lncRNAs expression profiles in tissue biopsies and urine of kidney transplant recipients with acute TCMR and identified three intergenic lncRNAs: LNC-MYH13-3:1, RP11-395P13.3-001 and RP11-354P17.15-001. They demonstrated that urinary RP11-354P17.15-001 can predict AR and loss of graft function at 1 year post transplantation. Also they showed that exposure of cultured tubular epithelial cells to the IL-6 as an inflammatory cytokine increased the expression levels of all lncRNAs, however, in the cell culture supernatant the expression levels of only RP11-395P13.3-001 and RP11-354P17.15-001were increased. The authors suggested that these lncRNAs might be secreted under inflammatory conditions (148).
In a study on a cohort of 72 patients with allograft rejection and 36 patients with SGF, lncRNA activated by transforming growth factor β (TGF-β) (lncRNA-ATB) was found to be significantly increased in biopsies of patients with AR compared with those with SGF. The authors stated that lncRNA-ATB could serve as a novel biomarker for AR, nephrotoxicity of immunosuppressive drugs and predict loss of graft function (149).
Evaluation of lncRNAs profile in peripheral blood of kidney transplant recipients was done by Ge et al. for the first time in cohorts of 150 pediatric and adult recipients. Among differentially expressed lncRNAs in pediatric and adult patients, 32 lncRNAs could distinguish both groups with AR from those without AR. Also, they showed that the two most significant lncRNAs, AF264622 and AB209021 had remarkable diagnostic values (AUC =0.829 and AUC =0.889, respectively) in both recipients groups for discriminating AR episodes from SGF (150).
Nagarajah et al. measured lncRNA, β-1, 4-mannosylglycoprotein 4-β-N-acetylglucosaminyltransferase antisense RNA1 (MGAT3-AS1) levels in mononuclear cells using QRT-PCR and showed that MGAT3-AS1 decreased significantly at first postoperative day after kidney transplantation. In addition, they observed an association between decreased level of MGAT3-AS1 and decreasing of plasma creatinine level within first day post transplantation and concluded that lncRNAs-MGAT3-AS1 assessment could be used for determining immediate allograft function (151).
Huang et al. showed that the serum concentration of interferon-induced protein 10 (IP-10) in acute TCMR episode was significantly higher compared with patients with SGF (152). There are numerous reports of fundamental role of IP-10 and its receptor CXCR3 in amplifying intragraft inflammation, enhancing inflammatory reactions via stimulating resident and alloreactive memory T-cells during rejection and ischemia induced tubular damage in human recipients as well as mouse and rat transplant models (152-157). On the other hand, increased levels of NF-κB resulted by reactive oxygen species and renal inflammation were seen (157,158). It was also documented that Arid2-IR lncRNA functions to promote NF-κB-dependent renal inflammatory cytokine expression (159). In a recent study, the regulatory effect of chemokine IP-10 on expression of Psoriasis susceptibility related RNA gene induced by stress (PRINS) lncRNAs was investigated (157). The increased levels of IP-10, NF-κB as well as up-regulation of PRINS lncRNAs were detected. Furthermore expression level of PRINS lncRNA was decreased following IP-10 antibody treatment was reported in the same study. The authors suggested that antibody treatment reduced T-cell recruitment and concluded that this might become indicative for PRINS lncRNA involvement in AR (157).
The success of organ transplantation as a preferred therapy is hindered by eventual failure of grafts mainly due to immune mediated rejection responses. Growing variety of human ncRNAs are emerged and their discoveries has opened a new window to biomedical research and toward pathogenesis of AR after transplantation. In AR the pathologic process can be detectable at molecular level before histological or clinical manifestations occur. Several investigations were done for profiling of miRNAs in biopsy, serum, plasma and urine samples of transplant recipients with AR to develop insights into pathways responsible for the rejection process and to find novel targets for therapy. However, till now involvement of only minority of lncRNAs in the pathogenesis of AR has been documented and other kinds of ncRNAs have not been identified yet in this aspect.
In this review list of miRNAs and lncRNAs have been linked to AR following kidney transplantation was presented and the usefulness of them as non-invasive biomarkers in early detection of AR was examined. The existence of a highly regulated interplay between mRNA/miRNAs/lncRNAs in allograft rejection mentioned in above studies lead to the notion that these ncRNAs might promote the identification of feasible biomarkers for monitoring the kidney allograft function, diagnosis, treatment and even preventing of AR occurrence. These could be achieved by further investigation of association between AR and ncRNAs to illuminate the mechanisms underlying the organ rejection.
The author thanks Prof. Dr. Ahad Jafari Ghods, MD, FACP, (Iran University of Medical Sciences) for critical reading and comments on the manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
- Meier-Kriesche HU, Ojo AO, Port FK, et al. Survival improvement among patients with end-stage renal disease: trends over time for transplant recipients and wait-listed patients. J Am Soc Nephrol 2001;12:1293-6. [PubMed]
- Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med 2010;363:1451-62. [Crossref] [PubMed]
- Heeger PS, Hricik D. Immune monitoring in kidney transplant recipients revisited J. Am. Soc. Nephrol 2002;13:288-90. [PubMed]
- Hardinger KL, Brennan DC. Novel immunosuppressive agents in kidney transplantation. World J Transplant 2013;3:68-77. [Crossref] [PubMed]
- Nankivell BJ, Borrows RJ, Fung CL, et al. Natural history, risk factors, and impact of subclinical rejection in kidney transplantation. Transplantation 2004;78:242-9. [Crossref] [PubMed]
- Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999;55:713-23. [Crossref] [PubMed]
- Girlanda R, Mannon RB, Kirk AD. Diagnostic tools for monitoring kidney transplant recipients. Semin Nephrol 2007;27:462-78. [Crossref] [PubMed]
- Schwarz A, Gwinner W, Hiss M, et al. Safety and adequacy of renal transplant protocol biopsies. Am J Transplant 2005;5:1992-6. [Crossref] [PubMed]
- Sanjeevani S, Pruthi S, Kalra S, et al. Role of neutrophil gelatinase-associated lipocalin for early detection of acute kidney injury. Int J Crit Illn Inj Sci 2014;4:223-8. [Crossref] [PubMed]
- Rysz J, Gluba-Brzózka A, Franczyk B, et al. Novel Biomarkers in the Diagnosis of Chronic Kidney Disease and the Prediction of Its Outcome. Int J Mol Sci 2017;18. [Crossref] [PubMed]
- Humar A, Hassoun A, Kandaswamy R, et al. Immunologic factors: the major risk for decreased long-term renal allograft survival. Transplantation 1999;68:1842-6. [Crossref] [PubMed]
- Goldberg RJ, Weng FL, Kandula P. Acute and chronic allograft dysfunction in kidney transplant recipients. Med Clin North Am 2016;100:487-503. [Crossref] [PubMed]
- Becker LE, Morath C, Suesal C. Immune mechanisms of acute and chronic rejection. Clin Biochem 2016;49:320-3. [Crossref] [PubMed]
- Wilflingseder J, Reindl-Schwaighofer R, Sunzenauer J, et al. MicroRNAs in kidney transplantation. Nephrol Dial Transplant 2015;30:910-7. [Crossref] [PubMed]
- Hamdorf M, Kawakita S, Everly M. The Potential of MicroRNAs as Novel Biomarkers for Transplant Rejection. J Immunol Res 2017;2017:4072364. [Crossref] [PubMed]
- Naesens M, Khatri P, Li L, et al. Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes. Kidney Int 2011;80:1364-76. [Crossref] [PubMed]
- Salvadori M, Tsalouchos A. Biomarkers in renal transplantation: An updated review. World J Transplant 2017;7:161-78. [Crossref] [PubMed]
- Ingulli E. Mechanism of cellular rejection in transplantation. Educational review. Pediatr Nephrol 2010;25:61-74. [Crossref] [PubMed]
- Hricik DE. Transplant Immunology and Immunosuppression: Core Curriculum 2015. Am J Kidney Dis 2015;65:956-66. [Crossref] [PubMed]
- Wang Y, Singh NK, Spear TT, et al. How an alloreactive T-cell receptor achieves peptide and MHC specificity. Proc Natl Acad Sci U S A 2017;114:E4792-E4801. [Crossref] [PubMed]
- Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 1987;165:302-19. [Crossref] [PubMed]
- Jenkins MK, Taylor PS, Norton SD, et al. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 1991;147:2461-6. [PubMed]
- Kearney ER, Walunas TL, Karr RW, et al. Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J Immunol 1995;155:1032-6. [PubMed]
- Krieger NR, Yin DP, Fathman CG. CD4+ but not CD8+ cells are essential for allorejection. J Exp Med 1996;184:2013-8. [Crossref] [PubMed]
- Hall BM. Cells mediating allograft rejection. Transplantation 1991;51:1141-51. [Crossref] [PubMed]
- Demirkiran A, Kok A, Kwekkeboom J, et al. Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transpl 2006;12:277-84. [Crossref] [PubMed]
- Meloni F, Vitulo P, Bianco AM, et al. Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome. Transplantation 2004;77:762-6. [Crossref] [PubMed]
- Salama AD, Najafian N, Clarkson MR, et al. Regulatory CD25+ T cells in human kidney transplant recipients. J Am Soc Nephrol 2003;14:1643-51. [Crossref] [PubMed]
- ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:57-74. [Crossref] [PubMed]
- Malone CD, Hannon GJ. Small RNAs as guardians of the genome. Cell 2009;136:656-68. [Crossref] [PubMed]
- Thomson T, Lin H. The biogenesis and function of PIWI proteins and piRNAs: progress and prospect. Annu Rev Cell Dev Biol 2009;25:355-76. [Crossref] [PubMed]
- Grosshans H, Filipowicz W. Molecular biology: the expanding world of small RNAs. Nature 2008;451:414-6. [Crossref] [PubMed]
- Fu XD. Non-coding RNA: a new frontier in regulatory biology. Natl Sci Rev 2014;1:190-204. [Crossref] [PubMed]
- Munshi A, Mohan V, Ahuja YR. Non-Coding RNAs: A Dynamic and Complex Network of Gene Regulation. J Pharmacogenomics Pharmacoproteomics 2016;7:156.
- Bhagavan NV. Chapter 25 - RNA and Protein Synthesis. In: Bhagavan NV. editor. Medical Biochemistry (Fourth Edition). Academic Press, 2002;563-91.
- Forbes DJ, Kornberg TB, Kirschner MW. Small nuclear RNA transcription and ribonucleoprotein assembly in early Xenopus development. J Cell Biol 1983;97:62-72. [Crossref] [PubMed]
- Dupuis-Sandoval F, Poirier M, Scott MS. The emerging landscape of small nucleolar RNAs in cell biology. Wiley Interdiscip Rev RNA 2015;6:381-97. [Crossref] [PubMed]
- Wilson DN, Doudna Cate JH. The structure and function of the eukaryotic ribosome. Cold Spring Harb Perspect Biol 2012;4. [Crossref] [PubMed]
- Anglicheau D, Muthukumar T, Suthanthiran M. MicroRNAs: small RNAs with big effects. Transplantation 2010;90:105-12. [Crossref] [PubMed]
- Kim VN. Small RNAs just got bigger: Piwi-interacting RNAs (piRNAs) in mammalian testes. Genes Dev 2006;20:1993-7. [Crossref] [PubMed]
- Claycomb JM. Ancient endo-siRNA pathways reveal new tricks. Curr Biol 2014;24:R703-715. [Crossref] [PubMed]
- Taft RJ, Glazov EA, Cloonan N, et al. Tiny RNAs associated with transcription start sites in animals. Nat Genet 2009;41:572-8. [Crossref] [PubMed]
- Kim TK, Hemberg M, Gray JM. Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers. Cold Spring Harb Perspect Biol 2015;7:a018622. [Crossref] [PubMed]
- Kapranov P, Cheng J, Dike S, et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 2007;316:1484-8. [Crossref] [PubMed]
- Affymetrix ENCODE Transcriptome Project. Cold Spring Harbor Laboratory ENCODE Transcriptome Project. Post-transcriptional processing generates a diversity of 5'-modified long and short RNAs. Nature 2009;457:1028-32. [Crossref] [PubMed]
- Kapranov P, Ozsolak F, Kim SW, et al. New class of gene-termini-associated human RNAs suggests a novel RNA copying mechanism. Nature 2010;466:642-6. [Crossref] [PubMed]
- Valen E, Preker P, Andersen PR, et al. Biogenic mechanisms and utilization of small RNAs derived from human protein-coding genes. Nat Struct Mol Biol 2011;18:1075-82. [Crossref] [PubMed]
- Core LJ, Waterfall JJ, Lis JT. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 2008;322:1845-8. [Crossref] [PubMed]
- Woo CJ, Kingston RE. HOTAIR lifts noncoding RNAs to new levels. Cell 2007;129:1257-9. [Crossref] [PubMed]
- Marahrens Y, Loring J, Jaenisch R. Role of the Xist gene in X chromosome choosing. Cell 1998;92:657-64. [Crossref] [PubMed]
- Yotova IY, Vlatkovic IM, Pauler FM, et al. Identification of the human homolog of the imprinted mouse Air non-coding RNA. Genomics 2008;92:464-73. [Crossref] [PubMed]
- Preker P, Almvig K, Christensen MS, et al. PROMoter uPstream Transcripts share characteristics with mRNAs and are produced upstream of all three major types of mammalian promoters. Nucleic Acids Res 2011;39:7179-93. [Crossref] [PubMed]
- Han J, Kim D, Morris KV. Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells. Proc Natl Acad Sci U S A 2007;104:12422-7. [Crossref] [PubMed]
- Yue X, Schwartz JC, Chu Y, et al. Transcriptional regulation by small RNAs at sequences downstream from 30 gene termini. Nat. Chem. Biol 2010;6:621-9. [Crossref] [PubMed]
- Scaruffi P. The transcribed-ultraconserved regions: a novel class of long noncoding RNAs involved in cancer susceptibility. ScientificWorldJournal 2011;11:340-52. [Crossref] [PubMed]
- Gao Y, Wang J, Zhao F. CIRI: an efficient and unbiased algorithm for de novo circular RNA identification. Genome Biol 2015;16:4. [Crossref] [PubMed]
- Greene J, Baird AM, Brady L, et al. Circular RNAs: Biogenesis, Function and Role in Human Diseases. Front Mol Biosci 2017;4:38. [Crossref] [PubMed]
- Weber JA, Baxter DH, Zhang S, et al. The microRNA spectrum in 12 body fluids. Clin Chem 2010;56:1733-41. [Crossref] [PubMed]
- Khurana R, Ranches G, Schafferer S, et al. Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease. RNA 2017;23:142-52. [Crossref] [PubMed]
- Xu T, Wu J, Han P, et al. Circular RNA expression profiles and features in human tissues: A study using RNA-seq data. BMC Genomics 2017;18:680. [Crossref] [PubMed]
- Kanki M, Moriguchi A, Sasaki D, et al. Identification of urinary miRNA biomarkers for detecting cisplatin-induced proximal tubular injury in rats. Toxicology 2014;324:158-68. [Crossref] [PubMed]
- Li YF, Jing Y, Hao J, et al. MicroRNA-21 in the pathogenesis of acute kidney injury. Protein &Cell 2013;4:813-9. [Crossref] [PubMed]
- Valadi H, Ekström K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654-9. [Crossref] [PubMed]
- Guay C, Regazzi R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat. Rev. Endocrinol 2013;9:513-21. [Crossref] [PubMed]
- Collino F, Bruno S, Incarnato D, et al. AKI recovery induced by mesenchymal stromal cell-derived extracellular vesicles carrying microRNAs. JASN 2015;26:2349-60. [Crossref] [PubMed]
- Zhang J, Li S, Li L, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics 2015;13:17-24. [Crossref] [PubMed]
- Bhatt K, Kato M, Natarajan R. Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 2016;310:F109-F118. [Crossref] [PubMed]
- Ambros V. The functions of animal microRNAs. Nature 2004;431:350-5. [Crossref] [PubMed]
- He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nature Reviews Genetics 2004;5:522-31. [Crossref] [PubMed]
- Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell 2012;148:1172-87. [Crossref] [PubMed]
- Huang JT, Wang J, Srivastava V, et al. MicroRNA machinery genes as novel biomarkers for cancer. Front Oncol 2014;4:113. [Crossref] [PubMed]
- Min PK, Chan SY. The biology of circulating microRNAs in cardiovascular disease. Eur J Clin Invest 2015;45:860-74. [Crossref] [PubMed]
- Xu C, Zhang L, Li H, et al. MiRNA-1469 promotes lung cancer cells apoptosis through targeting STAT5a. Am J Cancer Res 2015;5:1180-9. [PubMed]
- Jafari Ghods F, Topal Sarikaya A, Arda N, et al. MiRNA and mRNA Profiling in Systemic Lupus Reveals a Novel Set of Cytokine - Related miRNAs and their Target Genes in Cases With and Without Renal Involvement. Kidney Blood Press Res 2017;42:1322-37. [Crossref] [PubMed]
- Du T, Zamore PD. microPrimer: the biogenesis and function of microRNA. Development 2005;132:4645-52. [Crossref] [PubMed]
- Carthew RW. Gene regulation by microRNAs. Curr Opin Genet Dev 2006;16:203-8. [Crossref] [PubMed]
- Brennecke J, Stark A, Russell RB, et al. Principles of microRNA-target recognition. PLoS Biol 2005;3:e85. [Crossref] [PubMed]
- Lim LP, Lau LN, Engelle GP, et al. Microarray analysis shows that some microRNAs down regulate large numbers of target mRNAs. Nature 2005;433:769-73. [Crossref] [PubMed]
- Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005;120:15-20. [Crossref] [PubMed]
- Goodrich JA, Kugel JF. From bacteria to humans, chromatin to elongation, and activation to repression: The expanding roles of noncoding RNAs in regulating transcription. Crit Rev Biochem Mol Biol 2009;44:3-15. [Crossref] [PubMed]
- Vitalone MJ, Sidgel TK, Salomonis N, et al. Transcriptional perturbations in graft rejection. Transplantation 2015;99:1882-93. [Crossref] [PubMed]
- van den Akker EK, Dor FJ, IJzermans JN, et al. MicroRNAs in kidney transplantation: living up to their expectations? J Transplant 2015;2015:354826. [Crossref] [PubMed]
- Nankivell BJ. microRNA in transplantation: small in name only. Transplantation 2015;99:1754-5. [Crossref] [PubMed]
- Housman G, Ulitsky I. Methods for distinguishing between protein-coding and long noncoding RNAs and the elusive biological purpose of translation of long noncoding RNAs. Biochim Biophys Acta 2016;1859:31-40. [Crossref] [PubMed]
- Andrews SJ, Rothnagel JA. Emerging evidence for functional peptides encoded by short open reading frames. Nat Rev Genet 2014;15:193-204. [Crossref] [PubMed]
- Goff LA, Rinn JL. Linking RNA biology to lncRNAs. Genome Res 2015;25:1456-65. [Crossref] [PubMed]
- Spurlock CF 3rd, Crooke PS 3rd, Aune TM. Biogenesis and transcriptional regulation of long non-coding RNAs in the human immune system. J Immunol 2016;197:4509-17. [Crossref] [PubMed]
- Massone S, Ciarlo E, Vella S, et al. NDM29, a RNA polymerase III-dependent non coding RNA, promotes amyloidogenic processing of APP and amyloid β secretion. Biochim Biophys Acta 2012;1823:1170-7. [Crossref] [PubMed]
- Yang L, Duff MO, Graveley BR, et al. Genomewide characterization of non-polyadenylated RNAs. Genome Biol 2011;12:R16. [Crossref] [PubMed]
- Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nature 2012;489:101-8. [Crossref] [PubMed]
- Iyer MK, Niknafs YS, Malik R, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 2015;47:199-208. [Crossref] [PubMed]
- St Laurent G, Wahlestedt C, Kapranov P. The Landscape of long noncoding RNA classification. Trends Genet 2015;31:239-51. [Crossref] [PubMed]
- Jarroux J, Morillon A, Pinskaya M. Chapter 1: History, Discovery, and Classification of lncRNAs. In: Rao MRS. editor. Advances in Experimental Medicine and Biology: Long Non-coding RNA Biology. Singapore: Springer Nature, 2017:1-46.
- Derrien T, Johnson R, Bussotti G, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 2012;22:1775-89. [Crossref] [PubMed]
- Alam T, Medvedeva YA, Jia H, et al. Promoter analysis reveals globally differential regulation of human long non-coding RNA and protein-coding genes. PLoS One 2014;9:e109443. [Crossref] [PubMed]
- Spurlock CF, Tossberg JT, Guo Y, et al. Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nat Commun 2015;6:6932. [Crossref] [PubMed]
- Hoffmann MJ, Dehn J, Droop J, et al. Truncated isoforms of lncRNA ANRIL are overexpressed in bladder cancer, but do not contribute to repression of INK4 tumor suppressors. Noncoding RNA 2015;1:266-84. [Crossref] [PubMed]
- Meseure D, Vacher S, Lallemand F, et al. Prognostic value of a newly identified MALAT1 alternatively spliced transcript in breast cancer. Br J Cancer 2016;114:1395-404. [Crossref] [PubMed]
- Haddad G, Kölling M, Lorenzen JM. The hypoxic kidney: pathogenesis and noncoding RNA-based therapeutic strategies. Swiss Med Wkly 2019;149:w14703. [PubMed]
- Giannakakis A, Zhang J, Jenjaroenpun P, et al. Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress. Sci Rep 2015;5:9737. [Crossref] [PubMed]
- Lorenzen JM, Thum T. Long noncoding RNAs in kidney and cardiovascular diseases. Nat Rev Nephrol 2016;12:360-73. [Crossref] [PubMed]
- Jiang C, Li Y, Zhao Z, et al. Identifying and functionally characterizing tissue-specific and ubiquitously expressed human lncRNAs. Oncotarget 2016;7:7120-33. [PubMed]
- Harrow J, Frankish A, Gonzalez JM, et al. GENCODE: the reference human genome annotation for the ENCODE project. Genome Res 2012;22:1760-74. [Crossref] [PubMed]
- Tsai MC, Manor O, Wan Y, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010;329:689-93. [Crossref] [PubMed]
- Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell 2011;43:904-14. [Crossref] [PubMed]
- Xiang JF, Yang L, Chen LL. The long noncoding RNA regulation at the MYC locus. Curr Opin Genet Dev 2015;33:41-8. [Crossref] [PubMed]
- Yang L, Lin C, Jin C, et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 2013;500:598-602. [Crossref] [PubMed]
- Xiao L, Wu J, Wang JY, et al. Long Noncoding RNA uc.173 Promotes Renewal of the Intestinal Mucosa by Inducing Degradation of MicroRNA 195. Gastroenterology 2018;154:599-611. [Crossref] [PubMed]
- Bayoumi AS, Sayed A, Broskova Z, et al. Crosstalk between long noncoding RNAs and MicroRNAs in health and disease. Int J Mol Sci 2016;17:356. [Crossref] [PubMed]
- Davidovich C, Zheng L, Goodrich KJ, et al. Promiscuous RNA binding by Polycomb repressive complex 2. Nat Struct Mol Biol 2013;20:1250-7. [Crossref] [PubMed]
- Engreitz JM, Haines JE, Perez EM, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 2016;539:452-5. [Crossref] [PubMed]
- Anderson KM, Anderson DM, McAnally JR, et al. Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development. Nature 2016;539:433-6. [Crossref] [PubMed]
- Toiber D, Leprivier G, Rotblat B. Editorial: Long noncoding RNA: noncoding and not coded. Cell Death Discovery 2017;3:16104. [Crossref] [PubMed]
- Kumar V, Westra HJ, Karjalainen J, et al. Human disease-associated genetic variation impacts large intergenic non-coding RNA expression. PLoS Genet 2013;9:e1003201. [Crossref] [PubMed]
- Monticelli S, Ansel KM, Xiao C, et al. MicroRNA profiling of the murine hematopoietic system. Genome Biol 2005;6:R71. [Crossref] [PubMed]
- Muthukumar T, Dadhania D, Ding R, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005;353:2342-51. [Crossref] [PubMed]
- Aquino-Dias EC, Joelsons G, da Silva DM, et al. Non-invasive diagnosis of acute rejection in kidney transplants with delayed graft function. Kidney Int 2008;73:877-84. [Crossref] [PubMed]
- Abd Elaziz MM, Bakry S. Validation of Urinary PD-1 and FOXP3 mRNA in a Cohort of Egyptian Renal Allograft Recipients. Ann Transplant 2016;21:17-24. [Crossref] [PubMed]
- Sui W, Dai Y, Huang Y, et al. Microarray analysis of MicroRNA expression in acute rejection after renal transplantation. Transpl Immunol 2008;19:81-5. [Crossref] [PubMed]
- Merkerova M, Belickova M, Bruchova H. Differential expression of microRNAs in hematopoietic cell lineages. Eur J Haematol 2008;81:304-10. [Crossref] [PubMed]
- Grigoryev YA, Kurian SM, Hart T, et al. MicroRNA regulation of molecular networks mapped by global microRNA, mRNA, and protein expression in activated T lymphocytes. J Immunol 2011;187:2233-43. [Crossref] [PubMed]
- Scian MJ, Maluf DG, David KG, et al. MicroRNA profiles in allograft tissues and paired urines associate with chronic allograft dysfunction with IF/TA. Am J Transplant 2011;11:2110-22. [Crossref] [PubMed]
- Ben-Dov IZ, Muthukumar T, Morozov P, et al. MicroRNA sequence profiles of human kidney allografts with or without tubulointerstitial fibrosis. Transplantation 2012;94:1086-94. [Crossref] [PubMed]
- Maluf DG, Dumur CI, Suh JL, et al. The urine microRNA profile may help monitor post-transplant renal graft function. Kidney Int 2014;85:439-49. [Crossref] [PubMed]
- Danger R, Pallier A, Giral M, et al. Upregulation of miR-142-3p in peripheral blood mononuclear cells of operationally tolerant patients with a renal transplant. J Am Soc Nephrol 2012;23:597-606. [Crossref] [PubMed]
- Soltaninejad E, Nicknam MH, Nafar M, et al. Differential expression of microRNAs in renal transplant patients with acute T-cell mediated rejection. Transpl Immunol 2015;33:1-6. [Crossref] [PubMed]
- Anglicheau D, Sharma VK, Ding R, et al. MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci U S A 2009;106:5330-5. [Crossref] [PubMed]
- Liu XY, Xu J. The role of miR-223 in the acute rejection after kidney transplantation. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2011;27:1121-3. [PubMed]
- Domenico TD, Joelsons G, Montenegro RM, et al. Upregulation of microRNA 142-3p in the peripheral blood and urinary cells of kidney transplant recipients with post-transplant graft dysfunction. Braz J Med Biol Res 2017;50:e5533. [Crossref] [PubMed]
- Danger R, Paul C, Giral M, et al. Expression of miR-142-5p in Peripheral Blood Mononuclear Cells from Renal Transplant Patients with Chronic Antibody-Mediated Rejection. PLoS One 2013;8:e60702. [Crossref] [PubMed]
- Glowacki F, Savary G, Gnemmi V, et al. Increased circulating miR-21 levels are associated with kidney fibrosis. PLoS One 2013;8:e58014. [Crossref] [PubMed]
- Lorenzen JM, Volkmann I, Fiedler J, et al. Urinary miR-210 as a mediator of acute T-cell mediated rejection in renal allograft recipients. Am J Transplant 2011;11:2221-7. [Crossref] [PubMed]
- Betts G, Shankar S, Sherston S, et al. Examination of serum miRNA levels in kidney transplant recipients with acute rejection. Transplantation 2014;97:e28-30. [Crossref] [PubMed]
- Liu X, Dong C, Jiang Z, et al. MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11. Exp Cell Res 2015;333:155-63. [Crossref] [PubMed]
- Lv LL, Cao YH, Ni HF, et al. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am J Physiol Renal Physiol 2013;305:F1220-7. [Crossref] [PubMed]
- Sui W, Lin H, Peng W, et al. Molecular dysfunctions in acute rejection after renal transplantation revealed by integrated analysis of transcription factor, microRNA and long noncoding RNA. Genomics 2013;102:310-22. [Crossref] [PubMed]
- Sui W, Yang M, Li F, et al. Serum microRNAs as new diagnostic biomarkers for pre- and post-kidney transplantation. Transplant Proc 2014;46:3358-62. [Crossref] [PubMed]
- Wilflingseder J, Regele H, Perco P, et al. miRNA profiling discriminates types of rejection and injury in human renal allografts. Transplantation 2013;95:835-41. [Crossref] [PubMed]
- Wilflingseder J, Sunzenauer J, Toronyi E, et al. Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles. PLoS One 2014;9:e104164. [Crossref] [PubMed]
- Tao J, Yang X, Han Z, et al. Serum MicroRNA-99a Helps Detect Acute Rejection in Renal Transplantation. Transplant Proc 2015;47:1683-7. [Crossref] [PubMed]
- Bruneau S, Woda CB, Daly KP, et al. Key Features of the Intragraft Microenvironment that Determine Long-Term Survival Following Transplantation. Front Immunol 2012;3:54. [Crossref] [PubMed]
- Bijkerk R, Florijn BW, Khairoun M, et al. Acute Rejection After Kidney Transplantation Associates With Circulating MicroRNAs and Vascular Injury. Transplant Direct 2017;3:e174. [Crossref] [PubMed]
- Cheng K, Wan J, Luo A, et al. Role of peripheral blood microRNA-181b in acute vascular rejection after renal transplantation. Int J Clin Exp Med 2018;11:728-34.
- Matz M, Heinrich F, Lorkowski C, et al. MicroRNA regulation in blood cells of renal transplanted patients with interstitial fibrosis/tubular atrophy and antibody-mediated rejection. PLoS One 2018;13:e0201925. [Crossref] [PubMed]
- Misra MK, Pandey SK, Kapoor R, et al. Genetic variants of MicroRNA-related genes in susceptibility and prognosis of end-stage renal disease and renal allograft outcome among north Indians. Pharmacogenet Genomics 2014;24:442-50. [Crossref] [PubMed]
- Chen W, Peng W, Huang J, et al. Microarray analysis of long non-coding RNA expression in human acute rejection biopsy samples following renal transplantation. Mol Med Rep 2014;10:2210-6. [Crossref] [PubMed]
- Mattick JS, Amaral PP, Dinger ME, et al. RNA regulation of epigenetic processes. Bioessays 2009;31:51-9. [Crossref] [PubMed]
- Lorenzen JM, Schauerte C, Kolling M, et al. Long Noncoding RNAs in Urine Are Detectable and May Enable Early Detection of Acute T Cell-Mediated Rejection of Renal Allografts. Clin Chem 2015;61:1505-14. [Crossref] [PubMed]
- Qiu J, Chen Y, Huang G, et al. Transforming growth factor‐β activated long non‐coding RNA ATB plays an important role in acute rejection of renal allografts and may impacts the postoperative pharmaceutical immunosuppression therapy. Nephrology 2017;22:796-803. [Crossref] [PubMed]
- Ge YZ, Xu T, Cao WJ, et al. A Molecular Signature of Two Long Non-Coding RNAs in Peripheral Blood Predicts Acute Renal Allograft Rejection. Cell Physiol Biochem 2017;44:1213-23. [Crossref] [PubMed]
- Nagarajah S, Rasmussen M, Tepel M. SP762, Change of Long Non-Coding RNA, MGAT3-AS1, in Patients before and after kidney transplantation. Nephrology Dialysis Transplantation 2018;33 suppl:i605. [Crossref]
- Huang H, Xu X, Yao C, et al. Serum levels of CXCR3 ligands predict T cell-mediated acute rejection after kidney transplantation. Mol Med Rep 2014;9:45-50. [Crossref] [PubMed]
- Segerer S, Cui Y, Eitner F, et al. Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis 2001;37:518-31. [Crossref] [PubMed]
- Kasimsetty SG, McKay DB. Ischemia as a factor affecting innate immune responses in kidney transplantation. Curr Opin Nephrol Hypertens 2016;25:3-11. [Crossref] [PubMed]
- Zhuang J, Shan Z, Ma T, et al. CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model. Exp Ther Med 2014;8:237-42. [Crossref] [PubMed]
- Zou XF, Song B, Duan JH, et al. Prolonged ischemia elicits acute allograft rejection involved in CXCR3 activation in rat kidney transplants. Transpl Immunol 2015;33:103-9. [Crossref] [PubMed]
- Zou XF, Song B, Duan JH, et al. PRINS Long Noncoding RNA Involved in IP-10eMediated AllograftRejection in Rat Kidney Transplant. Transplant Proc 2018;50:1558-65. [Crossref] [PubMed]
- Ratliff BB, Abdulmahdi W, Pawar R, et al. Oxidant Mechanisms in Renal Injury and Disease. Antioxid Redox Signal 2016;25:119-46. [Crossref] [PubMed]
- Zhou Q, Huang XR, Yu J, et al. Long Noncoding RNA Arid2-IR Is a Novel Therapeutic Target for Renal Inflammation. Mol Ther 2015;23:1034-43. [Crossref] [PubMed]
Cite this article as: Jafari Ghods F. Trends of non-coding RNAs research in acute rejection after kidney transplantation. Non-coding RNA Investig 2019;3:16.