title: Parallel microarray profiling identifies ErbB4 as a determinant of cyst growth in ADPKD and a prognostic biomarker for disease progression.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common cause of end-stage renal disease. The disease course can be highly variable and treatment options are limited. To identify new therapeutic targets and prognostic biomarkers of disease, we conducted parallel discovery microarray profiling in normal and diseased humanPKD1cystic kidney cells. A total of 1,515 genes and 5 miRNA were differentially expressed by more than twofold inPKD1cells. Functional enrichment analysis identified 30 dysregulated signaling pathways including the epidermal growth factor (EGF) receptor pathway. In this paper, we report that the EGF/ErbB family receptor ErbB4 is a major factor driving cyst growth in ADPKD. Expression of ErbB4 in vivo was increased in human ADPKD andPkd1cystic kidneys, both transcriptionally and posttranscriptionally by mir-193b-3p. Ligand-induced activation of ErbB4 drives cystic proliferation and expansion suggesting a pathogenic role in cystogenesis. Our results implicate ErbB4 activation as functionally relevant in ADPKD, both as a marker of disease activity and as a new therapeutic target in this major kidney disease.
authors.affiliation: Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom; a.j.streets@sheffield.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Streets
authors.affiliation: Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom.
authors.forename: Tajdida A
authors.initials: TA
authors.lastname: Magayr
authors.affiliation: Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom.
authors.forename: Linghong
authors.initials: L
authors.lastname: Huang
authors.affiliation: Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Vergoz
authors.affiliation: Division of Nephrology, Mayo Clinic and Foundation, Rochester, Minnesota; and.
authors.forename: Sandro
authors.initials: S
authors.lastname: Rossetti
authors.affiliation: Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom.
authors.forename: Roslyn J
authors.initials: RJ
authors.lastname: Simms
authors.affiliation: Division of Nephrology, Mayo Clinic and Foundation, Rochester, Minnesota; and.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
authors.affiliation: Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom.
authors.forename: Albert C M
authors.initials: AC
authors.lastname: Ong
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods*; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020890:Neuregulin-1 / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D066247:Receptor, ErbB-4 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000172:deficiency / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
chemical_list: D005819:Genetic Markers; D035683:MicroRNAs; D020890:Neuregulin-1; D066247:Receptor, ErbB-4; D050396:TRPP Cation Channels; C546818:MIRN193 microRNA, human; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse
keywords: ADPKD; ErbB4 microRNA; polycystin