| Why is D-serine nephrotoxic and alpha-aminoisobutyric acid protective? | |
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MedLine Citation:
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PMID: 17429029 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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D-Serine selectively causes necrosis of S(3) segments of proximal tubules in rats. This leads to aminoaciduria and glucosuria. Coinjection of the nonmetabolizable amino acid alpha-aminoisobutyric acid (AIB) prevents the tubulopathy. D-serine is selectively reabsorbed in S(3), thereby gaining access to peroxisomal D-amino acid oxidase (D-AAO). D-AAO-mediated metabolism produces reactive oxygen species. We determined the fractional excretion of amino acids and glucose in rats after intraperitoneal injection of d-serine alone or together with reduced glutathione (GSH) or AIB. Both compounds prevented the hyperaminoaciduria. We measured GSH concentrations in renal tissue before (control) and after D-serine injection and found that GSH levels decreased to approximately 30% of control. This decrease was prevented when equimolar GSH was coinjected with D-serine. To find out why AIB protected the tubule from D-serine toxicity, we microinfused D-[(14)C]serine or [(14)C]AIB (0.36 mmol/l) together with [(3)H]inulin in late proximal tubules in vivo and measured the radioactivity in the final urine. Fractional reabsorption of D-[(14)C]serine and [(14)C]AIB amounted to 55 and 70%, respectively, and 80 mmol/l of AIB or D-serine mutually prevented reabsorption to a great extent. D-AAO activity measured in vitro (using D-serine as substrate) was not influenced by a 10-fold higher AIB concentration. We conclude from these results that 1) D-AAO-mediated d-serine metabolism lowers renal GSH concentrations and thereby provokes tubular damage because reduction of reactive oxygen species by GSH is diminished and 2) AIB prevents d-serine-induced tubulopathy by inhibition of D-serine uptake in S(3) segments rather than by interfering with intracellular D-AAO-mediated D-serine metabolism. |
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Authors:
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Alexander W Krug; Katharina Völker; William H Dantzler; Stefan Silbernagl |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-04-11 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 293 ISSN: 1931-857X ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2007 Jul |
Date Detail:
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Created Date: 2007-07-09 Completed Date: 2007-08-17 Revised Date: 2011-04-28 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F382-90 Citation Subset: IM |
Affiliation:
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Physiologisches Institut der Universität Würzburg, Röntgenring 9, D-97070 Würzburg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acids
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blood Aminoisobutyric Acids / therapeutic use* Animals D-Amino-Acid Oxidase / antagonists & inhibitors Dose-Response Relationship, Drug Glucose / metabolism Glutathione / metabolism Glycosuria / chemically induced Hydrogen Peroxide / metabolism Injections, Intraperitoneal Insulin / diagnostic use Kidney / drug effects, metabolism Kidney Diseases / chemically induced*, pathology, prevention & control* Kidney Tubules, Proximal / cytology, drug effects, metabolism Loop of Henle / drug effects, metabolism Male Oxidation-Reduction Rats Rats, Wistar Serine / administration & dosage, metabolism, toxicity* |
| Grant Support | |
ID/Acronym/Agency:
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DK-16294/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids; 0/Aminoisobutyric Acids; 11061-68-0/Insulin; 50-99-7/Glucose; 56-45-1/Serine; 62-57-7/2-aminoisobutyric acid; 70-18-8/Glutathione; 7722-84-1/Hydrogen Peroxide; EC 1.4.3.3/D-Amino-Acid Oxidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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