5/6 nephrectomy (5/6Nx) effect on the liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35135 | GEO | 2013/08/01
SECONDARY ACCESSION(S): PRJNA155993
REPOSITORIES: GEO
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Project description:Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYPs), but the mechanisms have been little explored. On the other hand, the expression of several CYP genes exhibits circadian rhythm. Here we report that downregulation of hepatic CYP3A11 (the murine homolog to human CYP3A4; the most decrease in 5/6Nx using microarray analysis) by suppressing the expression of clock gene; D-site binding protein (DBP). In vivo experiments, the mRNA levels of hepatic CYP3A11 exhibit circadian rhythm regulated by DBP and E4BP4, and significantly decreased in 5/6Nx. Microarray analysis revealed that the general transcription factors of CYP3A11 did not changed. However, DBP were downregulated and several CYP genes controlled by DBP also significantly decreased in 5/6Nx. These downregulations were not observed in angiotensin II type 1alpha receptor (AT II R1a) deficient 5/6Nx because serum TGF-betaM-BM- was not upregulate. In vitro experiments, the RNA levels of CYP3A11 and DBP were downregulated in wild-type mouse hepatocytes incubated with serum from 5/6Nx, but did not changed in Id2 (-/-) hepatocytes. In fact, hepatic Id2 was upregulated and caused the downregulation of DBP in 5/6Nx. Hepatocyte treated with SD208 (TGF-beta receptor 1 selectivity inhibitor) recovered CYP3A11, DBP and Id2 to control levels. Furthermore, 5/6Nx treated with tranilast (inhibitor of TGF-beta production or isolation) or candesartan (ARBs) also recovered CYP3A11 levels. Our findings define that DBP has effects on downregulation of CYP3A11. In CRF conditions, TGF-beta is upregulated by angiotensin II receptor in renal and downregulates DBP and CYP3A11 levels mediated by Id2 in liver. Furthermore, downregulation of CYP3A11 can prevent by tranilast or candesartan. Differential gene expression between 5/6 nephrectomized and sham-operated mouse was measured on the liver.
2013-08-01 | E-GEOD-35135 | biostudies-arrayexpress
Project description:The circadian clock has been found to be associated with various diseases. We showed that 5/6 nephrectomy (5/6Nx) Clk/Clk mice, which show mutation in the gene encoding circadian locomotor output cycles (Clock) do not show aggravation of renal fibrosis because transforming growth factor-1 (Tgf-1) expression is not increased. In wild-type 5/6Nx kidneys, we found that retinoid, a metabolite of retinol, led to alteration of the expresion 24-h rhythm of Clock expression. Renal Tgf- 1 expression is activated by Clock and further aggravates renal dysfunction by causing fibrosis. We also showed that, in 5/6Nx mice fed a retinol-free diet, renal fibrosis and apoptosis are reduced, leading to a marked improvement in serum creatinine levels. Moreover, our study identified hepatic Cyp3a11 and Cyp26a1 as key retinol metabolism-related genes whose expression decreased in 5/6Nx mice. Our data indicated that the negative chain reaction of metabolic clock alteration in between the kidney and liver aggravates renal dysfunction. Differential gene expression between retinol (-) feeding and clock mutant in 5/6 nephrectomized mouse was measured on the kidney at 8 weeks after operation. Four-week-old male ICR mice (Charles River Japan, Inc., Yokohama, Japan) were housed in a light-controlled room (lights on from Zeitgeber time [ZT] 0 to ZT12) at 24 ± 1°C and 60 ± 10% humidity, with food and water available ad libitum. Mice were synchronized to the lighting conditions for 2 weeks before surgery. Male ICR mice (5 weeks old) were purchased from Charles River Japan, Inc. (Kanagawa, Japan). Clock mutant mice (C57BL/6J-ClockmlJt/J) were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). We placed them in the ICR genetic background to enhance breeding robustness and care of the young. These mice were backcrossed using a Jcl:ICR background for more than eight generations. We prepared mouse models of CRF by 5/6Nx operation (Ope) under sodium pentobarbital (40 mg/kg, i.p.) or diethyl ether anesthesia. 5/6Nx was performed in two stages. In the first surgical procedure (at 6 weeks of age), two-thirds of the left kidney was removed by cutting off both poles. Seven days later, the right kidney was completely removed. After the operation, mice were housed for 8 weeks (until they were 16 weeks old) in order to achieve CRF. Sham-operated (Sham) mice were subjected to laparotomy on the same days as the procedure in the 5/6Nx mice. This method was also used for treating Clk/Clk mice. Retinol-free food (A minus) was purchased form KBT ORIENTAL CO., LTD. To investigate the influences of retinol-free feeding on kidney, mice were fed from the fourth week to the eighth week after an operation.
2014-06-06 | E-GEOD-57799 | biostudies-arrayexpress
Project description:The circadian clock has been found to be associated with various diseases. We showed that 5/6 nephrectomy (5/6Nx) Clk/Clk mice, which show mutation in the gene encoding circadian locomotor output cycles (Clock) do not show aggravation of renal fibrosis because transforming growth factor-1 (Tgf-1) expression is not increased. In wild-type 5/6Nx kidneys, we found that retinoid, a metabolite of retinol, led to alteration of the expresion 24-h rhythm of Clock expression. Renal Tgf- 1 expression is activated by Clock and further aggravates renal dysfunction by causing fibrosis. We also showed that, in 5/6Nx mice fed a retinol-free diet, renal fibrosis and apoptosis are reduced, leading to a marked improvement in serum creatinine levels. Moreover, our study identified hepatic Cyp3a11 and Cyp26a1 as key retinol metabolism-related genes whose expression decreased in 5/6Nx mice. Our data indicated that the negative chain reaction of metabolic clock alteration in between the kidney and liver aggravates renal dysfunction.
2014-06-06 | GSE57799 | GEO
Project description:Th9 cells are differentiated from naïve CD4+ T cells by T cell receptor (TCR) stimulation in the presence of the cytokines transforming growth factor-beta (TGF-b) and IL-4, but the molecular mechanisms by which signaling via these two cytokines control Il9 gene expression remain incompletely understood. We show here opposing functions of albumin site D-binding protein (DBP) and E2F8, an atypical member of the E2F family member of transcription factors , in controlling Th9 cell differentiation. Specifically, TGF-b and IL-4 signaling induced phosphorylation of the Serine 213 site in the linker region of the Smad3 protein (pSmad3L-Ser213) via the activation of phosphorylated MAPK p38 (p-p38). pSmad3L-Ser213, but not the phosphorylation of the C-terminal of SMAD3 (pSmad3C), was necessary and sufficient for Il9 gene transcription. We identified DBP and E2F8 as a potential activator and repressor, respectively, for Il9 gene transcription by analyzing the global chromatin accessibility and transcriptomes and discovered that pSmad3L-Ser213 was required for the increase in DBP expression but decreased E2F8 expressions during Th9 cell differentiation. We found that while DBP and E2F8 directly bound to the promoters of Il9 gene, DBP enhanced, but E2F8 suppressed, Il9 gene transcription in CD4+ T cells in response to TGF-b and IL-4 signaling, as revealed by functional gene loss- and gain-of-function studies. Notably, the Dbp-deficient and E2f8-deficient Th9 cells promoted and suppressed tumor growth, respectively, in experimental tumor models of melanoma and fibrosarcoma in mice. Importantly, DBP and E2F8 also exhibited opposing roles in regulating human TH9 differentiation in vitro. Thus, we have revealed a previously unrecognized molecular mechanism of Smad3 linker region-mediated opposing functions of DBP and E2F8 in Th9 differentiation.
2022-08-09 | GSE182472 | GEO
Project description:Transforming growth factor-beta (TGF-beta) transmits signals that facilitate cancer progression. Especially, epithelial-mesenchymal transition (EMT) induced by TGF-beta is considered to crucially contribute to the malignant phenotype of cancer cells. Here we report that the EMT-associated cellular responses induced by TGF-beta are mediated through distinct signaling pathways that diverge at Smad3; cell motility and epithelial marker downregulation are Smad3-dependent while mesenchymal marker induction is not. Furthermore, using a chimeric protein approach in SMAD3 knockout A549 cells, we found that the beta 4 region in the MH1 domain of Smad3 is indispensable for TGF-beta–induced cell motility, but not for epithelial marker downregulation. A transcriptome analysis was performed using A549 cells expressing Smad3 mutant of the MH1 domain.
2021-03-10 | GSE152015 | GEO
Project description:RATIONALE: Measuring levels of transforming growth factor-beta (TGF-beta) in the blood of patients with epithelial cancers (head and neck, lung, breast, colorectal, and prostate) may help doctors predict how patients will respond to treatment with radiation therapy.
PURPOSE: This research study is measuring levels of TGF-beta in patients with epithelial cancers who are undergoing radiation therapy.
| 2072028 | ecrin-mdr-crc
Project description:Introduction Iodine-131 (131I) is frequently used in nuclear medicine. Unbound or released 131I accumulate in the thyroid gland and may be detrimental to normal thyroid function. The aim of the present study was to identify biomarkers for 131I exposure in rat thyroid tissue and to assess the effect on thyroid function. Methods Thirty six male Sprague Dawley rats were i.v. injected with 150 µl saline solution containing 9.0, 88, 170, 260, 340, 760, 1300, or 4700 kBq (group A-H) 131I, or mock-treated with 150 µl saline solution only, and killed at 24 h after injection. Total RNA was extracted from individual thyroid tissue samples thyroids and mRNA levels were determined with the Agilent microarray platform. Results Estimated absorbed doses in treatment groups A-H was 0.0058, 0.057, 0.11, 0.17, 0.22, 0.5 Gy, 0.8 Gy, and 3 Gy. Totally, 429 transcripts were identified with a fold change fold change ⥠1.5 and adjusted p-value ⤠0.01. A trend with downregulation of thyroid hormone biosynthesis associated genes (e.g. thyroglobulin, thyroid peroxidase, the sodium-iodine symporter) was identified, but only statistically significant after 0.0058 and 0.22 Gy. Three transcripts coding for isoform 1 of the DBP protein showed a pattern with monotonous decrease in downregulation with absorbed dose between 0.0058-0.22 Gy. Changes in Dbp expression were not statistically significant between 0.5-3 Gy. However, a trend with downregulation at 0.5 and 0.8 Gy and upregulation and 3 Gy was identified. Previously, 131I (0.85-17 Gy) and 211At (0.023-32 Gy) exposure resulted in upregulation of Dbp in mice thyroid tissue 24 h after administrations. Additionally, a monotonous decrease in Dbp downregulation has been identified of in mouse kidney tissue at 8 and 12 months after 177Lu-octreotate administrations. Conclusion Conclusively, the Dbp gene is a promising candidate biomarker gene for exposure to 131I and possibly other internal radiation emitters. Further studies should be performed to establish how Dbp expression vary with dose-rate, absorbed dose, time after administration, different radiation qualities, and the function of Dbp. Total RNA was isolated from fresh-frozen individual thyroid tissue samples (Sprague Dawley rats). Each sample was run once. Four rats received the same treatment. Control samples (from non-irradiated rats) are included.
2016-06-30 | E-GEOD-66623 | biostudies-arrayexpress
Project description:Introduction Iodine-131 (131I) is frequently used in nuclear medicine. Unbound or released 131I accumulate in the thyroid gland and may be detrimental to normal thyroid function. The aim of the present study was to identify biomarkers for 131I exposure in rat thyroid tissue and to assess the effect on thyroid function. Methods Thirty six male Sprague Dawley rats were i.v. injected with 150 µl saline solution containing 9.0, 88, 170, 260, 340, 760, 1300, or 4700 kBq (group A-H) 131I, or mock-treated with 150 µl saline solution only, and killed at 24 h after injection. Total RNA was extracted from individual thyroid tissue samples thyroids and mRNA levels were determined with the Agilent microarray platform. Results Estimated absorbed doses in treatment groups A-H was 0.0058, 0.057, 0.11, 0.17, 0.22, 0.5 Gy, 0.8 Gy, and 3 Gy. Totally, 429 transcripts were identified with a fold change fold change ≥ 1.5 and adjusted p-value ≤ 0.01. A trend with downregulation of thyroid hormone biosynthesis associated genes (e.g. thyroglobulin, thyroid peroxidase, the sodium-iodine symporter) was identified, but only statistically significant after 0.0058 and 0.22 Gy. Three transcripts coding for isoform 1 of the DBP protein showed a pattern with monotonous decrease in downregulation with absorbed dose between 0.0058-0.22 Gy. Changes in Dbp expression were not statistically significant between 0.5-3 Gy. However, a trend with downregulation at 0.5 and 0.8 Gy and upregulation and 3 Gy was identified. Previously, 131I (0.85-17 Gy) and 211At (0.023-32 Gy) exposure resulted in upregulation of Dbp in mice thyroid tissue 24 h after administrations. Additionally, a monotonous decrease in Dbp downregulation has been identified of in mouse kidney tissue at 8 and 12 months after 177Lu-octreotate administrations. Conclusion Conclusively, the Dbp gene is a promising candidate biomarker gene for exposure to 131I and possibly other internal radiation emitters. Further studies should be performed to establish how Dbp expression vary with dose-rate, absorbed dose, time after administration, different radiation qualities, and the function of Dbp.
2016-06-30 | GSE66623 | GEO
Project description:Based on studies in knockout mice, several inhibitory factors such as TGF-beta, IL-10, or CTLA-4 have been implicated as gate keepers of adaptive immune responses. Lack of these inhibitory molecules leads to massive inflammatory responses mainly mediated by activated T cells. In humans, the integration of these inhibitory signals for keeping T cells at a resting state is less well understood. To elucidate this regulatory network we assessed early genome-wide transcriptional changes during serum deprivation in human mature CD4+ T cells. The most striking observation was a "TGF-beta loss signature" defined by downregulation of many known TGF-beta target genes. Moreover, numerous novel TGF-beta target genes were identified that are under the suppressive control of TGF-beta. Expression of these genes was upregulated once TGF-beta signaling was lost during serum deprivation and again suppressed upon TGF-beta reconstitution. Constitutive TGF-beta signaling was corroborated by demonstrating phosphorylated SMAD2/3 in resting human CD4+ T cells in situ, which were dephosphorylated during serum deprivation and re-phosphorylated by minute amounts of TGF-beta. Loss of TGF-beta signaling was particularly important for T cell proliferation induced by low-level T cell receptor and costimulatory signals. We suggest TGF-beta to be the most prominent factor actively keeping human CD4+ T cells at a resting state. Keywords: time course, dose response
2007-05-01 | GSE7497 | GEO
Project description:Oral squamous cell carcinoma (OSCC) has a very poor prognosis due to its highly invasive nature, and 5-year survival rate has not changed apparently for the past 30 years. Although cylindromatosis (CYLD) is thought as a potent tumor suppressor, its biological and clinical significances in OSCC are largely unknown. The aim of this study was to clarify roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed that CYLD expression was significantly reduced at invasive lesions in OSCC tissues whereas it was conserved in normal epithelium and carcinoma in situ. Accordingly, downregulation of CYLD by siRNA led to an acquisition of mesenchymal state and increased migratory and invasive activities in OSCC cells and HaCaT keratinocytes. Interestingly, CYLD knockdown promoted TGF-beta signaling by inducing TGF-beta receptor I (ALK5) stabilization in a cell autonomous fashion. In addition, the response to exogenous TGF-beta stimulation was enhanced by CYLD downregulation. The invasive phenotype induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. Furthermore, lower CYLD expression was significantly associated with deep invasion, poor overall survival, and increased Smad3 phosphorylation which is an indicator of TGF-beta signaling activation in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells.
2017-06-29 | GSE100589 | GEO