Abstract
The (pro)renin receptor ((P)RR) signaling is involved in different pathophysiologies ranging from cardiorenal end-organ damage via diabetic retinopathy to tumorigenesis. We have previously shown that the transcription factor promyelocytic leukemia zinc finger (PLZF) is an adaptor protein of the (P)RR. Furthermore, recent publications suggest that major functions of the (P)RR are mediated ligand-independently by its transmembrane and intracellular part, which acts as an accessory protein of V-ATPases. The transcriptome and recruitmentome downstream of the V-ATPase function and PLZF in the context of the (P)RR are currently unknown. Therefore, we performed a set of microarray and chromatin-immunoprecipitation (ChIP)-chip experiments using siRNA against the (P)RR, stable overexpression of PLZF, the PLZF translocation inhibitor genistein and the specific V-ATPase inhibitor bafilomycin to dissect transcriptional pathways downstream of the (P)RR. We were able to identify distinct and overlapping genetic signatures as well as novel real-time PCR-validated target genes of the different molecular functions of the (P)RR. Moreover, bioinformatic analyses of our data confirm the role of (P)RŔs signal transduction pathways in cardiovascular disease and tumorigenesis.
MeSH terms
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Cardiovascular Diseases / genetics*
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Cardiovascular Diseases / metabolism
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Chromatin Immunoprecipitation
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Gene Expression Regulation / drug effects
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Genistein / pharmacology
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HEK293 Cells
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Humans
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Kruppel-Like Transcription Factors / antagonists & inhibitors
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Kruppel-Like Transcription Factors / genetics*
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Kruppel-Like Transcription Factors / metabolism
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Macrolides / pharmacology
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Oligonucleotide Array Sequence Analysis
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Promyelocytic Leukemia Zinc Finger Protein
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Prorenin Receptor
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Protein Kinase Inhibitors / pharmacology
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RNA, Small Interfering / genetics
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Receptors, Cell Surface / antagonists & inhibitors
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / metabolism
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Signal Transduction / drug effects
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Transcriptome*
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Vacuolar Proton-Translocating ATPases / antagonists & inhibitors
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Vacuolar Proton-Translocating ATPases / genetics*
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Vacuolar Proton-Translocating ATPases / metabolism
Substances
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Kruppel-Like Transcription Factors
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Macrolides
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Promyelocytic Leukemia Zinc Finger Protein
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Receptors, Cell Surface
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ZBTB16 protein, human
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bafilomycin A1
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Genistein
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Vacuolar Proton-Translocating ATPases
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Prorenin Receptor
Grants and funding
Mr. Mirko Schlawinsky, and Mrs. Nadine Genzel (ImaGenes GmbH, Berlin, Germany) and Dr. Nancy Bretschneider (Genomatix GmbH, Munich, Germany) helped with the ChIP-chip hybridization and/or the primary data analyses. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.