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Change in expression of genes after retinoic acid treatment of stellate cells: dose response

ABSTRACT: We evaluated the change in expression of genes after treatment of stellate cells with retinoic acid to understand how the stellate cells can de-differentiate and effect their physiological behaviour in pathological conditions. We then tested the changes in the gene expression in 2D and 3D culture conditions for pancreatic stellate cells and in a pancreatic cancer model. Keywords: gene expression change, dose response, matrix conditions We treated a pancreatic stellate cell line on plastic or Matrigel with 1 or 10 micromolar dose of all-trans retinoic acid (ATRA). RNA was extracted and hybridized on Illumina Human microarrays. We looked for target genes regulated by ATRA and evaluated for dose repsonse and change due to background culture conditions.

ORGANISM(S): Homo sapiens

SUBMITTER: Kocher Hemant

PROVIDER: S-ECPF-GEOD-14425 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BackgroundVitamin A is necessary for kidney development and has also been linked to regulation of solute and water homeostasis and to protection against kidney stone disease, infection, inflammation, and scarring. Most functions of vitamin A are mediated by its main active form, all-trans retinoic acid (tRA), which binds retinoic acid receptors (RARs) to modulate gene expression. We and others have recently reported that renal tRA/RAR activity is confined to the ureteric bud (UB) and collecting duct (CD) cell lineage, suggesting that endogenous tRA/RARs primarily act through regulating gene expression in these cells in embryonic and adult kidney, respectively.Methodology/principal findingsTo explore target genes of endogenous tRA/RARs, we employed the mIMCD-3 mouse inner medullary CD cell line, which is a model of CD principal cells and exhibits constitutive tRA/RAR activity as CD principal cells do in vivo. Combining antagonism of RARs, inhibition of tRA synthesis, exposure to exogenous tRA, and gene expression profiling techniques, we have identified 125 genes as candidate targets and validated 20 genes that were highly regulated (Dhrs3, Sprr1a, and Ppbp were the top three). Endogenous tRA/RARs were more important in maintaining, rather than suppressing, constitutive gene expression. Although many identified genes were expressed in UBs and/or CDs, their exact functions in this cell lineage are still poorly defined. Nevertheless, gene ontology analysis suggests that these genes are involved in kidney development, renal functioning, and regulation of tRA signaling.Conclusions/significanceA rigorous approach to defining target genes for endogenous tRA/RARs has been established. At the pan-genomic level, genes regulated by endogenous tRA/RARs in a CD cell line have been catalogued for the first time. Such a catalogue will guide further studies on molecular mediators of endogenous tRA/RARs during kidney development and in relation to renal defects associated with vitamin A deficiency.

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Change in expression of genes after retinoic acid treatment of stellate cells: dose response

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