Regulation of the hepatic synthesis of α<sub>2u</sub> globulin and its corresponding messenger RNA in maturing male rats

Roy, Arun K.; Schiop, Michael J.; Dowbenko, Donald

doi:10.1016/0014-5793(76)80743-0

Cited by 30 publications

(4 citation statements)

References 29 publications

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“…They are capable of binding PFOA in vitro , although the binding affinity is relatively weak [56]. The globulin A2U L is synthesized exclusively in the liver of adult male rats [57], secreted into the blood stream, and freely filtered by the glomerulus [58]. Approximately 50% of the filtered proteins are excreted in urine and form the major component of male rat urinary proteins.…”

Section: Discussionmentioning

confidence: 99%

Biological Responses to Perfluorododecanoic Acid Exposure in Rat Kidneys as Determined by Integrated Proteomic and Metabonomic Studies

et al. 2011

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BackgroundPerfluorododecanoic acid (PFDoA) is a perfluorinated carboxylic chemical (PFC) that has broad applications and distribution in the environment. While many studies have focused on hepatotoxicity, immunotoxicity, and reproductive toxicity of PFCAs, few have investigated renal toxicity.Methodology/Principal FindingsHere, we used comparative proteomic and metabonomic technologies to provide a global perspective on renal response to PFDoA. Male rats were exposed to 0, 0.05, 0.2, and 0.5 mg/kg/day of PFDoA for 110 days. After 2-D DIGE and MALDI TOF/TOF analysis, 79 differentially expressed proteins between the control and the PFDoA treated rats (0.2 and 0.5 mg-dosed groups) were successfully identified. These proteins were mainly involved in amino acid metabolism, the tricarboxylic acid cycle, gluconeogenesis, glycolysis, electron transport, and stress response. Nuclear magnetic resonance-based metabonomic analysis showed an increase in pyruvate, lactate, acetate, choline, and a variety of amino acids in the highest dose group. Furthermore, the profiles of free amino acids in the PFDoA treated groups were investigated quantitatively by high-coverage quantitative iTRAQ-LC MS/MS, which showed levels of sarcosine, asparagine, histidine, 1-methylhistidine, Ile, Leu, Val, Trp, Tyr, Phe, Cys, and Met increased markedly in the 0.5 mg dosed group, while homocitrulline, α-aminoadipic acid, β-alanine, and cystathionine decreased.Conclusion/SignificanceThese observations provide evidence that disorders in glucose and amino acid metabolism may contribute to PFDoA nephrotoxicity. Additionally, α2u globulin may play an important role in protecting the kidneys from PFDoA toxicity.

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Section: Discussionmentioning

confidence: 99%

Biological Responses to Perfluorododecanoic Acid Exposure in Rat Kidneys as Determined by Integrated Proteomic and Metabonomic Studies

et al. 2011

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“…The system involves androgen-dependent synthesis of a low molecular weight (23,000) protein called a2u globulin (10, 11). We have also identified the mRNA for a2u globulin in rat liver and have established a strong correlation between the androgen-dependent increase in a2u synthesis and the hepatic concentration of the mRNA for this protein (9,12,13 Cycloheximide, cordycepin, and a-amanitin were administered in 0.14 M NaCl. All of these chemicals were administered by intraperitoneal injections.…”

Section: Introductionmentioning

confidence: 92%

“…However, it should be pointed out that an overwhelming body of data indicates that both steroid and nonsteroid hormones are involved in the regulation of gene transcription in their target cells (12,13,21,24,(37)(38)(39)(40)(41)(42). These two apparently contradictory conclusions can be reconciled if one considers that the post-transcriptional regulation serves only as an additional control over the transcriptional regulation and could play an important physiological role in the suppression of "leaky" genes.…”

Section: Effect Of Actinomycinmentioning

confidence: 99%

Superinduction of alpha 2u globulin by actinomycin D: evidence for drug-mediated increase in alpha 2u mRNA.

Chatterjee

Hopkins

Dutchak

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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Actinomycin D, an inhibitor of DNA-dependent RNA synthesis, increased the hepatic concentration of a2u globulin, an androgen-inducible protein in the rat. Spayed female rats with a marginally induced state of a2u synthesis showed an approximately 5-fold increase in hepatic a2u globulin within 3-6 hr after treatment with actinomycin D. Initial treatment of these animals with 5a-dihydrotestosterone, followed by actinomycin D, resulted within 2-3 hr in a more than 2-fold increase in hepatic a2u globulin compared to animals treated with the androgen alone. In spite of inhibition of hepatic synthesis of poly(A)containing RNA to less than 25% of control, superinduction with actinomycin D resulted in a parallel increase in the translatable mRNA for a2u globulin. These results showing increase in both a2u globulin and its translatable mRNA after superinduction with actinomycin D support the concept of post-transcriptional repression of a2u synthesis. Actinomycin D, an inhibitor of DNA-dependent RNA synthesis, increases the level of several inducible proteins, a phenomenon termed "superinduction" (1, 2). Because actinomycin D inhibits mRNA synthesis, superinduction by this drug indicates an apparent paradox, the resolution of which may provide important clues concerning the mechanism of gene regulation in the eukaryotic cell. In fact, the post-transcriptional model for the steroidal regulation of gene activity, proposed by Tomkins and coworkers, is based primarily on their interpretation of the superinduction of glucocorticoid-mediated synthesis of tyrosine aminotransferase (TAT) by actinomycin D in hepatoma cells and in rat liver (3). A similar model of translational repression was also suggested by McAuslan (4). The above investigators have proposed that the mRNAs for the inducible proteins are continually being synthesized within the permissive phase of the cell cycle. However, the simultaneous presence of rapidly turning over post-transcriptional repressors prevents the translation of these mRNAs and may lead to their degradation. It is also proposed that, in the presence of inducing steroids, the repressor is inactivated and, because of its short half-life, is preferentially eliminated by actinomycin D, both of which phenomena would favor an accumulation of the inducible mRNA leading to increased synthesis of the inducible protein (3). Due to technical limitations, experimental verification of the McAuslan-Tomkins model has been difficult, and various other interpretations for the phenomenon of superinduction by actinomycin D have been proposed (5-7).In our laboratory we have developed a model system for the study of hormone action in rat liver (8, 9). The system involves androgen-dependent synthesis of a low molecular weight (23,000) protein called a2u globulin (10, 11). We have also identified the mRNA for a2u globulin in rat liver and have established a strong correlation between the androgen-dependent increase in a2u synthesis and the hepatic concentration of the mRNA for this protein (9,12,13 Cyclohexim...

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“…Hyaline droplets in male rats are frequently associated with a 2u -globulin accumulation. a 2u -globulin is a low molecular weight protein synthesized by the liver of male rats but not female rats (16,18,19,21). The function of this protein is not known, but under normal conditions it is ltered at the glomerulus and reabsorbed by the proximal tubule (2,19,21).…”

Section: Introductionmentioning

confidence: 99%

p-Nitrobenzoic Acid α2u Nephropathy in 13-week Studies is not Associated with Renal Carcinogenesis in 2-year Feed Studies

et al. 2001

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The objective of this study was to characterize the renal toxicity and carcinogenicity of p-nitrobenzoi c acid in F344 rats. Dose levels in 13-week and 2-year studies ranged from 630-10,000 ppm and 1,250-5,000 ppm, respectivel y. At 13 weeks, renal lesions included minimal to mild hyaline droplet accumulation in male rats and karyomegal y in male and female rats. At 2 years, renal lesions included proximal tubule epithelial cell hyperplasia in male rats and oncocytic hyperplasia in high-dose male and female rats, and a decreased severity of nephropathy in males and females. The hyaline droplets in renal tubular epithelial cells of male rats at 13 weeks were morphologicall y similar to those described in a 2u -globulin nephropathy. Using immunohistochemica l methods, a 2u -globulin accumulation was associated with the hyaline droplets. In addition, at 13 weeks, cell proliferation as detected by PCNA immunohistochemistr y was signi cantly increased in males exposed to 5,000 and 10,000 ppm when compared to controls. Cytotoxicity associated with a 2u -globulin nephropath y such as single-cell necrosis of the P2 segment epithelium or accumulation of granular casts in the outer medulla did not occur in the 13-week study. In addition, chronic treatment related nephrotoxic lesions attributed to accumulation of a 2u -globulin such as linear foci of mineralization within the renal papilla, hyperplasia of the renal pelvis urothelium and kidney tumors were not observed. Although there was histologic evidence of a 2u -globulin accumulation in male rats at 13 weeks, the minimal severity of nephropath y suggests that the degree of cytotoxicity was below the threshold, which would contribute to the development of renal tumors at 2 years.

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Regulation of the hepatic synthesis of α_2u globulin and its corresponding messenger RNA in maturing male rats

Cited by 30 publications

References 29 publications

Biological Responses to Perfluorododecanoic Acid Exposure in Rat Kidneys as Determined by Integrated Proteomic and Metabonomic Studies

Biological Responses to Perfluorododecanoic Acid Exposure in Rat Kidneys as Determined by Integrated Proteomic and Metabonomic Studies

Superinduction of alpha 2u globulin by actinomycin D: evidence for drug-mediated increase in alpha 2u mRNA.

p-Nitrobenzoic Acid α2u Nephropathy in 13-week Studies is not Associated with Renal Carcinogenesis in 2-year Feed Studies

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Regulation of the hepatic synthesis of α2u globulin and its corresponding messenger RNA in maturing male rats

Cited by 30 publications

References 29 publications

Biological Responses to Perfluorododecanoic Acid Exposure in Rat Kidneys as Determined by Integrated Proteomic and Metabonomic Studies

Biological Responses to Perfluorododecanoic Acid Exposure in Rat Kidneys as Determined by Integrated Proteomic and Metabonomic Studies

Superinduction of alpha 2u globulin by actinomycin D: evidence for drug-mediated increase in alpha 2u mRNA.

p-Nitrobenzoic Acid α2u Nephropathy in 13-week Studies is not Associated with Renal Carcinogenesis in 2-year Feed Studies

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Regulation of the hepatic synthesis of α_2u globulin and its corresponding messenger RNA in maturing male rats