Why is D-serine nephrotoxic and alpha-aminoisobutyric acid protective?
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.
Krug
Alexander W
AW
Physiologisches Institut der Universität Würzburg, Röntgenring 9, D-97070 Würzburg, Germany.
Völker
Katharina
K
Dantzler
William H
WH
Silbernagl
Stefan
S
D000596:Amino Acids / Q000097:blood; D000621:Aminoisobutyric Acids / Q000627:therapeutic use*; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006029:Glycosuria / Q000139:chemically induced; D006861:Hydrogen Peroxide / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007328:Insulin; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008138:Loop of Henle / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
D000596:Amino Acids; D000621:Aminoisobutyric Acids; D007328:Insulin; C100049:2-aminoisobutyric acid; D012694:Serine; D006861:Hydrogen Peroxide; D003605:D-Amino-Acid Oxidase; D005978:Glutathione; D005947:Glucose