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Abnormal Mir-148B Expression Promotes Aberrant Glycosylation of Iga1 in Iga Nephropathy

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Abnormal Mir-148B Expression Promotes Aberrant Glycosylation of Iga1 in Iga Nephropathy BASIC RESEARCH www.jasn.org Abnormal miR-148b Expression Promotes Aberrant Glycosylation of IgA1 in IgA Nephropathy † † Grazia Serino,* Fabio Sallustio,* Sharon N. Cox,* Francesco Pesce,* and † Francesco P. Schena* *Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy; and †Centro Addestramento Ricerca Scientifica in Oncologia (C.A.R.S.O.) Consortium, Valenzano, Italy ABSTRACT Aberrant O-glycosylation in the hinge region of IgA1 characterizes IgA nephropathy. The mechanisms underlying this abnormal glycosylation are not well understood, but reduced expression of the enzyme core 1, b1,3-galactosyltransferase 1 (C1GALT1) may contribute. In this study, high-throughput microRNA (miRNA) profiling identified 37 miRNAs differentially expressed in PBMCs of patients with IgA nephrop- athy compared with healthy persons. Among them, we observed upregulation of miR-148b, which poten- tially targets C1GALT1. Patients with IgA nephropathy exhibited lower C1GALT1 expression, which negatively correlated with miR-148b expression. Transfection of PBMCs from healthy persons with a miR-148b mimic reduced endogenous C1GALT1 mRNA levels threefold. Conversely, loss of miR-148b function in PBMCs of patients with IgA nephropathy increased C1GALT1 mRNA and protein levels to those observed in healthy persons. Moreover, we found that upregulation of miR-148b directly correlated with levels of galactose-deficient IgA1. In vitro, we used an IgA1-producing cell line to confirm that miR-148b modulates IgA1 O-glycosylation and the levels of secreted galactose-deficient IgA1. Taken together, these data suggest a role for miRNAs in the pathogenesis of IgA nephropathy. Abnormal expression of miR-148b may explain the aberrant glycosylation of IgA1, providing a potential pharmacologic target for IgA nephropathy. J Am Soc Nephrol 23: ccc–ccc, 2012. doi: 10.1681/ASN.2011060567 IgA nephropathy (IgAN) is considered the most IgAN is a complex multifactorial disease whose common form of primary GN throughout the pathogenic mechanism is still unknown. Several world, and about 40% of patients develop ESRD.1,2 investigators have sought to identify specific genetic The initial event in the pathogenesis of IgAN is markers associated with the development and pro- the mesangial deposition of IgA1, aberrantly gly- gression of this disease;15 however, few studies have cosylated because the hinge-region O-linked gly- specifically described intracellular mechanisms as- cans lack galactose.3–6 Different studies suggest that sociated with disease development.16 Recently, our this alteration could lead to IgA1 self-aggregation,7 group identified new mechanisms associated with IgA1-IgG immune complex formation,8,9 and com- plex defective clearance, with sequential deposition in the glomeruli.10 Received June 13, 2011. Accepted December 19, 2011. In humans, each IgA1 heavy-chain hinge region G.S. and F.S. contributed equally to this work. fi has three to ve 5 O-linked glycans that are built Published online ahead of print. Publication date available at by stepwise addition of monosaccharides, begin- www.jasn.org. ning with the addition of N-acetylgalactosamine Correspondence: Dr. Francesco P. Schena, Nephrology Dialysis by the enzyme N-acetylgalactosaminyltransferase and Transplantation Unit, Department of Emergency and Organ 2 and continuing with the addition of galactose Transplantation, University of Bari, Policlinico, Piazza G. Cesare bytheenzymecore1,b1,3-galactosyltransferase 1 no. 11, 70124, Bari, Italy. Email: [email protected] – (C1GALT1).11 14 Copyright © 2012 by the American Society of Nephrology J Am Soc Nephrol 23: ccc–ccc, 2012 ISSN : 1046-6673/2305-ccc 1 BASIC RESEARCH www.jasn.org the pathogenesis of IgAN and showed that WNT-b-catenin and PI3K/Akt pathways were highly activated in patients with IgAN.17 The basis for the abnormal glycosylation in IgAN is still unknown, but some studies suggest that C1GALT1 could be involved because of its altered expression.18 On the other hand, the potential role of microRNAs (miRNAs) in the IgAN pathogenesis has been poorly in- vestigated. After the discovery of miRNAs, great effort has focused on determining their biologic functions and their relevance to diseases. In fact, deregulation of miRNAs has been associated with several disease states, including kidney diseases.19 To our knowledge, this study is the first to evaluate the global miRNA expression profile of IgAN patients9 PBMCs, which are directly involved in the disease.20 We defined the miRNA signature in patients with IgAN and showed that miR-148b regulating C1GALT1 explains the abnormal glycosylation pro- cess in IgAN. These results support an important and unre- ported role of this miRNA in the pathogenesis of IgAN and suggest a pharmacologic rationale for the potential use of syn- thetic miRNA inhibitors to attenuate IgA1 deglycosylation in the disease. RESULTS Figure 1. Unsupervised hierarchical clustering of miRNA ex- pression profile. miRNA expression pattern of PBMCs of seven Identification of Differentially Expressed miRNAs in patients with IgAN and seven healthy subjects (HSs) were ex- Patients with IgAN amined using Agilent array composed of 723 human and 76 The role of miRNA expression in the pathogenesis of IgAN human viral miRNAs. A total of 147 miRNAs were expressed in all samples, discriminating patients with IgAN from HSs (P,0.0001; has not been well explored. To identify miRNAs differentially , fi fi FDR 0.01). Two principal clusters were identi ed on the basis of expressed in IgAN, we analyzed their global expression pro le differential miRNA expression. in PBMCs of seven patients with IgAN and seven healthy participants. Among 723 human miRNAs represented on the microarrays, 147 were expressed in each sample. Unsupervised hierarchical clustering analysis generated a tree with the IgAN target genes of the 35 upregulated miRNAs. To reduce the and healthy participants clearly separated into two groups number of false-positive results, we used four different (Figure 1). This separation was further confirmed by display- algorithms and listed only putative target genes predicted by ing the relationships among miRNA expression patterns using at least two of them. On the basis of the results of bioinfor- principal component analysis (Supplemental Figure 1). After matics analysis, we found that one of the potential targets of we applied a fold change threshold . 2 (false discovery rate miR-148b was the gene C1GALT1, which plays an important [FDR], 0.01), 35 miRNAs were found to be significantly up- role in the pathogenesis of IgAN. Of note, other miR-148b regulated and 2 were significantly downregulated in IgAN (Sup- putative target genes were inversin (INVS) and phosphatase plemental Table 1). To validate microarray results, we and tensin homologue (PTEN) (Supplemental Table 2), two performed quantitative real-time PCR (qRT-PCR) for miR- genes that we found downregulated in patients with IgAN.17 148b, miR-188-5p, miR-361-3p, miR-886-3p, let-7b, and let-7d Ingenuity Pathway Analysis (IPA) software was then used to on miRNAs isolated from PBMCs of an independent set of 10 evaluate the biologic interaction among miRNAs. Weuploaded patients with IgAN and 10 healthy persons with the same clini- the 35 upregulated miRNAs in IPA, and two networks were cal and demographic characteristics as those in the population identified. When we merged each of them with the network used for microarray experiments (Table 1). The expression of all resulting from the gene expression profile published in our analyzed miRNAs was significantly higher in patients with IgAN, previous work,17 we found that miRNAs were strongly inter- thereby confirming microarray results (Figure 2, A and B). connected with the mRNA network (Supplemental Figure 2). In particular, let-7d directly regulated PTEN, miR-361 regu- In silico Analysis of miRNA Targets lated INVS, miR-148b regulated both INVS and PTEN,and To study the molecular mechanisms in which the miRNAs are three miRNAs (let-7d, let-7a, miR-98) indirectly regulate AKT involved, we performed a bioinformatic analysis to predict through RET. 2 Journal of the American Society of Nephrology J Am Soc Nephrol 23: ccc–ccc,2012 www.jasn.org BASIC RESEARCH Table 1. Demographic and clinical features of patients and healthy participants Initial Sample Cohort Disease Controls Validation Sample Cohort Variable Healthy Healthy IgAN MPGN-I FSGS HSPN IgAN Participants Participants Participants (n) 25 25 3 5 10 50 50 Men/women (n/n)16∕915∕10 2/1 3/2 5/5 38/12 40/10 Age (yr) 37.2610.2 36.1610.6 3569.6 42612.3 8.56336612.3 43610.6 Serum creatinine (mg/dl) 0.960.2 0.860.3 0.760.05 0.860.4 0.560.1 1.0060.5 0.960.3 Estimate GFR (ml/min per 1.73 m2)118622.3 106613.1 122610 116.8611 ND 120611 114612.3 Proteinuria (g/24 h) 0.360.1 0.160.2 2.761.2 2.0560.9 ND 0.860.2 0.0660.02 Systolic BP (mmHg) 121620.4 120610 133611.5 126615 118616 124613.3 11969 Diastolic BP (mmHg) 726974688060.5 7966.5 6768 77.269.7 7469 Total IgA (ng/ml) 0.1060.004 0.1260.01 ND ND 0.1560.01 0.1460.002 0.1360.001 Unless otherwise noted, values are expressed as mean 6 SD. IgAN, IgA nephropathy; MPGN-I, membranoproliferative GN type I; FSGS, focal segmental glomerulosclerosis; HSPN, Henoch-Schönlein purpura nephritis; ND, not determined. miR-148b levels in patients with IgAN and the healthy participants. A negative corre- lation was observed (R2=0.4; P,0.01; Fig- ure 4C): samples with higher miR-148b expression levels showed lower levels of C1GALT1 mRNA. The inverse correlation observed be- tween the levelsofmiR-148bandC1GALT1 mRNA suggests that this gene is probably a target of miR-148b. Moreover, we performed a bioinformatic Figure 2. Differential expression validation. Validation of differential expression of miR-148b, miR-188-5p, miR-886-3p, let-7b, and let-7d (A) and miR-361-3p (B) in an analysis to estimate the effect of some single- independent set of PBMCs from 10 patients with IgAN and 10 healthy subjects (HSs).
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