Inhibition of renal gluconeogenesis in rats by ochratoxin.
Ontology highlight
ABSTRACT:
SUBMITTER: Meisner H
PROVIDER: S-EPMC1161111 | biostudies-other | 1979 Jun
REPOSITORIES: biostudies-other
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Project description:This study is to develop a short term and highly accurate prediction method of renal carcinogenicity based on gene expression profile of rats administrated by carcinogens. We conducted 28 days-repeated dose experiments in male SD rats with ochratoxin A, and the gene expression profiles of renal cortex were analyzed using custom microarrays.
2016-09-27 | GSE87263 | GEO
Project description:The mycotoxin ochratoxin A (OTA) is a potent nephrocarcinogen, mainly in male rats. The aim of this study was to determine the time course of gene expression (GeneChip® Rat Gene 2.0 ST Array, Affymetrix) in kidney samples from male and female F344 rats, treated daily (p.o) with 0.50 mg/kg b.w. (body weight) of OTA for 7 or 21 days, and evaluate if there were differences between both sexes. After OTA treatment, there was an evolution of gene expression in the kidney over time, with more differentially expressed genes (DEG) at 21 days. The gene expression time course was different between sexes with respect to the number of DEG and the direction of expression (up or down): the female response was progressive and consistent over time, whereas males had a different early response with more DEG, most of them up-regulated. The statistically most significant DEG corresponded to metabolism enzymes (Akr1b7, Akr1c2, Adh6 down-regulated in females; Cyp2c11, Dhrs7, Cyp2d1, Cyp2d5 down-regulated in males) or transporters (Slc17a9 down-regulated in females; Slco1a1 (OATP-1) and Slc51b and Slc22a22 (OAT) down-regulated in males). Some of these genes had also a basal sex difference and were over-expressed in males or females with respect to the other sex.
| S-EPMC7996782 | biostudies-literature
Project description:Inhibition of gluconeogenesis with 3-mercaptopicolinate in suckling newborn rats caused a fall in blood [glucose], but no change in their high plasma [free fatty acid] and blood [ketone bodies]. Active gluconeogenesis seems to be more important than sparing of glucose by high concentrations of fat-derived substrates for the maintenance of normal blood [glucose] in suckling newborn rats.
| S-EPMC1164587 | biostudies-other
Project description:BACKGROUND: Nephrotoxicity is the most prominent one among the various toxicities of ochratoxin A (OTA). MicroRNAs (miRNAs) are small non-coding RNAs that have an impact on a wide range of biological processes by regulating gene expression at post-transcriptional level or protein systhesis level. The objective of this study is to analyze miRNA profiling in the kidneys of rats gavaged with OTA. RESULTS: To profile miRNAs in the kidneys of rats with OTA nephrotoxicity, high-throughput sequencing and bioinformatics approaches were applied to analyze the miRNAs in the kidney of rats following OTA treatment. A total of 409 known miRNAs and 8 novel miRNAs were identified in the kidney and the levels of the novel miRNAs were varied in response to different doses of OTA. Expression of miR-129, miR-130a, miR-130b, miR-141, miR-218b and miR-3588 were uniquely suppressed in mid dose but then elevated in high dose, with opposite expression to their target genes. The expression pattern was closely related with the "MAPK signaling pathway". Dicer1 and Drosha were significantly suppressed, indicating an impairment of miRNA biogenesis in response to OTA. CONCLUSIONS: The abrogation of miRNA maturation process suggests a new target of OTA toxicity. Moreover, the identification of the differentially expressed miRNAs provides us a molecular insight into the nephrtoxicity of OTA.
| S-EPMC4035064 | biostudies-literature
Project description:The objective of this study is to analyze miRNA profiling in the kidneys of rats gavaged with OTA. To profile miRNAs in the kidneys of rats with OTA nephrotoxicity, high-throughput sequencing and bioinformatics approaches were applied to analyze the miRNAs in the kidney of rats following OTA treatment
2014-06-01 | E-MTAB-2475 | biostudies-arrayexpress
Project description:Experiments were performed in which the effects of inhibiting gluconeogenesis on ketone-body formation were examined in vivo in starved and severely streptozotocin-diabetic rats. The infusion of 3-mercaptopicolinate, an inhibitor of gluconeogenesis (DiTullio et al., 1974), caused decreases in blood [glucose] and increases in blood [lactate] and [pyruvate] in both normal and ketoacidotic rats. Patterns of liver gluconeogenic intermediates after 3-mercaptopicolinate infusion suggested inhibition at the level of phosphoenolpyruvate carboxykinase. This was confirmed by measurement of hepatic oxaloacetate concentrations which were increased 5-fold after 3-mercaptopicolinate administration. The infusion of 3-mercaptopicolinate caused a decrease in total ketone-body concentrations of 30% in starved rats and 73% in the diabetic animals. Blood glycerol and hepatic triglyceride concentrations remained unchanged. The decreases in ketone-body concentrations were associated with increases in the calculated hepatic cytosolic and mitochondrial [NADH]/[NAD+] ratios. The decrease in ketogenesis seen after inhibition of gluconeogenesis may have resulted from an inhibition of hepatic fatty acid oxidation by the more reduced mitochondrial redox state. It was concluded that gluconeogenesis may stimulate ketogenesis by as much as 30% in severe diabetic ketoacidosis.
| S-EPMC1165552 | biostudies-other
Project description:The fasting-activated longevity protein sirtuin 1 (SirT1, ref. 1) promotes gluconeogenesis in part, by increasing transcription of the key gluconeogenic genes pepck1 and g6pase, through deacetylating PGC-1alpha and FOXO1 (ref. 4). In contrast, signal transducer and activator of transcription 3 (STAT3) inhibits glucose production by suppressing expression of these genes. It is not known whether the inhibition of gluconeogenesis by STAT3 is controlled by metabolic regulation. Here we show that STAT3 phosphorylation and function in the liver were tightly regulated by the nutritional status of an animal, through SirT1-mediated deacetylation of key STAT3 lysine sites. The importance of the SirT1-STAT3 pathway in the regulation of gluconeogenesis was verified in STAT3-deficient mice in which the dynamic regulation of gluconeogenic genes by nutritional status was disrupted. Our results reveal a new nutrient sensing pathway through which SirT1 suppresses the inhibitory effect of STAT3, while activating the stimulatory effect of PGC-1alpha and FOXO1 on gluconeogenesis, thus ensuring maximal activation of gluconeogenic gene transcription. The connection between acetylation and phosphorylation of STAT3 implies that STAT3 may have an important role in other cellular processes that involve SirT1.
| S-EPMC2790597 | biostudies-literature
Project description:Oxidative stress and apoptosis are involved in Ochratoxin A (OTA)-induced renal cytotoxicity. Apoptosis signal-regulating kinase 1 (ASK1) is a Mitogen-Activated Protein Kinase Kinase Kinase (MAPKKK, MAP3K) family member that plays an important role in oxidative stress-induced cell apoptosis. In this study, we performed RNA interference of ASK1 in HEK293 cells and employed an iTRAQ-based quantitative proteomics approach to globally investigate the regulatory mechanism of ASK1 in OTA-induced renal cytotoxicity. Our results showed that ASK1 knockdown alleviated OTA-induced ROS generation and ??m loss and thus desensitized the cells to OTA-induced apoptosis. We identified 33 and 24 differentially expressed proteins upon OTA treatment in scrambled and ASK1 knockdown cells, respectively. Pathway classification and analysis revealed that ASK1 participated in OTA-induced inhibition of mRNA splicing, nucleotide metabolism, the cell cycle, DNA repair, and the activation of lipid metabolism. We concluded that ASK1 plays an essential role in promoting OTA-induced renal cytotoxicity.
| S-EPMC5389036 | biostudies-literature
Project description:Aims/introductionBacterial septicemia has diverse clinical symptoms including severe hypoglycemia. However, sepsis-induced hypoglycemia has not yet been examined in detail. The aim of the present study was to investigate the mechanisms underlying hypoglycemia in sepsis.Materials and methodsWe induced endotoxin shock in rats using lipopolysaccharide (LPS). After an intraperitoneal injection of LPS, we measured gluconeogenesis using the pyruvate tolerance test. The effects of LPS on glucose metabolism were investigated in perfused livers and isolated hepatocytes. Furthermore, its effects on the production of inflammatory cytokines were examined in isolated splenocytes. The interaction between splenocytes and hepatocytes in response to LPS was investigated in vitro using a co-culture of splenocytes and hepatocytes.ResultsIn the pyruvate tolerance test, the pretreatment with LPS decreased gluconeogenesis. The in vivo pretreatment of rats with LPS did not inhibit glucose production in perfused livers. The in vitro treatment of isolated hepatocytes with LPS did not decrease hepatic gluconeogenesis. Although LPS increased the production of inflammatory cytokines (tumor necrosis factor-?, interferon-?, interleukin-1?, interleukin-6 and interleukin-10) and nitric oxide in isolated splenocytes, only nitric oxide significantly inhibited gluconeogenesis in isolated hepatocytes. When splenocytes and hepatocytes were co-cultured in medium containing LPS, the messenger ribonucleic acid expression of glucose-6-phosphatase in hepatocytes was suppressed.ConclusionsLPS reduced hepatic gluconeogenesis, at least in part, by stimulating the production of nitric oxide in splenocytes. This effect could contribute to the mechanisms responsible for septicemia-induced hypoglycemia.
| S-EPMC5934270 | biostudies-literature
Project description:BACKGROUND:Therapies targeting altered activity of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) have been proposed for hepatomas. However, the activities of these pathways in hepatomas in vivo have not been distinguished. Here we examined pyruvate entry into the tricarboxylic acid (TCA) cycle through PDH versus PC in vivo using hepatoma-bearing rats. METHODS:Hepatoma-bearing rats were generated by intrahepatic injection of H4IIE cells. Metabolism of 13C-labeled glycerol, a physiological substrate for both gluconeogenesis and energy production, was measured with 13C NMR analysis. The concentration of key metabolites and the expression of relevant enzymes were measured in hepatoma, surrounding liver, and normal liver. RESULTS:In orthotopic hepatomas, pyruvate entry into the TCA cycle occurred exclusively through PDH and the excess PDH activity compared to normal liver was attributed to downregulated pyruvate dehydrogenase kinase (PDK) 2/4. However, pyruvate carboxylation via PC and gluconeogenesis were minimal, which was linked to downregulated forkhead box O1 (FoxO1) by Akt activity. In contrast to many studies of cancer metabolism, lactate production in hepatomas was not increased which corresponded to reduced expression of lactate dehydrogenase. The production of serine and glycine in hepatomas was enhanced, but glycine decarboxylase was downregulated. CONCLUSIONS:The combination of [U-13C3]glycerol and NMR analysis enabled investigation of multiple biochemical processes in hepatomas and surrounding liver. We demonstrated active PDH and other related metabolic alterations in orthotopic hepatomas that differed substantially not only from the host organ but also from many earlier studies with cancer cells.
| S-EPMC6892165 | biostudies-literature