title: Massive analysis of cDNA Ends (MACE) and miRNA expression profiling identifies proatherogenic pathways in chronic kidney disease.
abstract: Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.
authors.affiliation: Department of Internal Medicine IV; Saarland University Medical Center; Homburg, Germany.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Zawada
authors.affiliation: Department of Internal Medicine IV; Saarland University Medical Center; Homburg, Germany.
authors.forename: Kyrill S
authors.initials: KS
authors.lastname: Rogacev
authors.affiliation: GenXPro GmbH; Frankfurt am Main, Germany; Molecular BioSciences; Biocenter; Johann Wolfgang Goethe University; Frankfurt am Main, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Müller
authors.affiliation: GenXPro GmbH; Frankfurt am Main, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rotter
authors.affiliation: GenXPro GmbH; Frankfurt am Main, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Winter
authors.affiliation: Department of Internal Medicine IV; Saarland University Medical Center; Homburg, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: Department of Internal Medicine IV; Saarland University Medical Center; Homburg, Germany.
authors.forename: Gunnar H
authors.initials: GH
authors.lastname: Heine
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism*; D018076:DNA, Complementary / Q000032:analysis* / Q000235:genetics; D020869:Gene Expression Profiling; D063990:Gene Ontology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D015398:Signal Transduction
chemical_list: D018076:DNA, Complementary; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D035683:MicroRNAs
keywords: MACE; atherosclerosis; cardiovascular disease; epigenetics; hemodialysis; kidney disease; miRNA; next-generation sequencing