Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of rat Tsc2 mutant (Eker) vs. wild type treated with aristolochic acid and ochratoxin A

ABSTRACT: Renal gene expression profiles of Eker and wild type rats, gavaged with AA or OTA, respectively for 1, 3, 7 or 14 days; We used Affymetrix RAE230A microarrays for the analysis of early gene expression changes in the renal cortex_ outer medulla of carcinogen treated Eker and corresponding wild type rats Experiment Overall Design: Eker and wild type rats were gavaged daily with OTA (210Âµg_ kg BW) or AA (10mg_ kg BW), dissolved in 0,1M sodium bicarbonate. Time-matched vehicle controls were gavaged with 0,1M sodium bicarbonate. Following 1, 3, 7, and 14 days of treatment, Narcoren (pentobarbital) anesthetized rats were sacrificed by exsanguination subsequent to retrograde perfusion with PBS. Left kidneys were collected, cross-sectioned into 5mm slices and stored in RNAlater for subsequent RNA isolantion and chip hybridisation

ORGANISM(S): Rattus norvegicus

SUBMITTER: Daniel Dietrich

PROVIDER: E-GEOD-5923 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis.

Stemmer Kerstin K Ellinger-Ziegelbauer Heidrun H Ahr Hans-Juergen HJ Dietrich Daniel R DR

Cancer research 20070501 9

Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogen-induced changes in gene expression. Male Eker and wild-type rats were gavaged daily wi ...[more]

PMID: 17483316

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Project description:Pulmonary hypertension (PH) and cancer pathophysiology share common signal transduction pathways leading to abnormal endothelial and smooth muscle cell interactions and angioproliferative vasculopathy. Sorafenib (Sor) a drug in clinical trials for cancer treatment, is an inhibitor of multiple kinases important in angiogenesis (Raf-1 kinase, VEGFR-2, VEGFR-3, PDGFR-ï¢)ï©. In this study, we assessed the efficacy of Sor as a potential therapy for PH, and hypothesized that Sor prevents the development of both a conventional and an augmented rodent model of PH. We performed studies in Dahl Salt-Sensitive rats (SS) exposed to hypoxia alone and in combination with the VEGFR-2 inhibitor, SU5416, known to induce a well-characterized augmented PH phenotype. Rats were, thus, divided into 5 groups: normoxia/vehicle (Norm), hypoxia/vehicle (H), hypoxia/ SU5416 (H-SU), hypoxia/Sorafenib (H-Sor) and hypoxia/ SU5416/ Sorafenib (H-SU-Sor). Except for the Norm group, all rats were maintained in a hypoxia chamber with a FiO2 of 10%. Rats received a single injection of SU5416 on Day 1 (20 mg/kg) and Sor solution was administered daily by gavage (2.5mg/kg). After 3.5 weeks, all rats were assessed by open chest catheterizations for pulmonary vascular and right ventricular pressures. Lung and heart tissue were harvested for histological and microarray analyses. Our results showed H-SU rats developed severe PH with changes in hemodynamic and histologic parameters when compared to Norm controls while rats exposed to H alone only displayed mildly elevated pressures compared with Norm. There was no significant change in pressures in the H-Sor or H-SU-Sor compared to Norm. Histopathology demonstrated a dramatic prevention of the PH phenotype in the H-SU-Sor rats with no significant remodeling compared with H-SU rats. Expression profiling data from H (n=4) and H-SU (n=3) rat lungs were compared to Norm (n=4) using normalization in R and SAM (Î´>.639,) (minimum fold change >1.4). With false discovery rates (FDR) of 6.5% in hypoxia and 1.6% in H-SU, 1019 and 465 genes, respectively, were differentially-regulated compared to Norm. In addition, 38 genes were differentially expressed between H-SU and H-SU-Sor (n=4, FDR 6.7%) revealing a molecular signature with potentially novel target genes of Sor. Five differentially expressed genes (Tgfï¢3, C1qg, Nexn, Frzb, and Plaur) were examined by real-time RT-PCR and three were further validated by immunohistochemistry confirming the regulation on protein level. Based on the known pathways of hypoxic-induced PH and Sor, we further utilized immunohistochemistry to show the up-regulation of mediators of the MAPK cascade in the H and H-SU models of PH with subsequent, down-regulation by Sor. We therefore present Sor as a novel treatment for the development of severe PH and theorize that the MAPK cascade is a canonical pathway involved both in the development of PH and in the attenuation by Sor. This SuperSeries is composed of the following subset Series:; GSE8078: A Multi- Kinase Inhibitor Modulates Pulmonary Hypertension in a Rodent Model 1; GSE8132: A Multi- Kinase Inhibitor Modulates Pulmonary Hypertension in a Rodent Model 2 Experiment Overall Design: Refer to individual Series

Dataset Information

Transcription profiling of rat Tsc2 mutant (Eker) vs. wild type treated with aristolochic acid and ochratoxin A

Publications

Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis.

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