<scp>d</scp>-Serine is reabsorbed in rat renal pars recta

Silbernagl, Stefan; Völker, Katharina; Dantzler, William H.

doi:10.1152/ajprenal.1999.276.6.f857

Cited by 40 publications

(48 citation statements)

References 23 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Direct D-serine administration may be problematic due to its accumulation in several tissues and nephrotoxic effects (41). Our results point to the feasibility of designing serine racemase ligands to stimulate Lserine racemization while impairing ␣,␤-elimination.…”

Section: Discussionmentioning

confidence: 81%

Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity

Foltyn

Bendikov

Miranda

et al. 2005

Journal of Biological Chemistry

201

196

View full text Add to dashboard Cite

D-Serine is a D-amino acid that occurs at high levels in the mammalian brain and is an endogenous ligand of the "glycine site" of N-methyl D-aspartate (NMDA) 1 receptors (1-4). NMDA receptors play key roles in excitatory synaptic transmission, plasticity, and learning and memory (5). Overactivation of the NMDA receptor and the resultant influx of calcium into cells is a major culprit in the cell death that occurs following stroke and neurodegenerative diseases. Blockers of the "glycine site" of the receptor are neuroprotective in animal models of stroke (5). Endogenous D-serine is required for NMDA receptor activation, and its removal markedly decreases NMDA receptor activity (3). In the vertebrate retina, endogenous D-serine may also mediate the light-dependent increase in neuronal activity by activating NMDA receptors (6). More recently, D-serine was suggested to play a role in the long term potentiation of synaptic transmission in the hippocampus, indicating a role of endogenous D-serine in long term synaptic plasticity (7).D-Serine is synthesized by serine racemase, a pyridoxal phosphate (PLP)-dependent enzyme enriched in the mammalian brain (8, 9). Serine racemase has high sequence homology with the fold-type II group of PLP enzymes, such as serine/threonine dehydratase and D-serine dehydratase (10, 11). In addition to converting L-to D-serine, serine racemase catalyzes the ␣,␤-elimination of water from L-serine to form pyruvate and ammonia (12). The initial rates of racemization and ␣,␤-elimination of L-serine by serine racemase are strongly stimulated by magnesium and ATP, indicating that the complex Mg⅐ATP is a physiological ligand of the enzyme (12).In accordance with accepted mechanisms of PLP-catalyzed reactions (13-16), a mechanism for racemization and ␣,␤-elimination catalyzed by serine racemase is depicted in Scheme 1. PLP, bound to the enzyme through an internal aldimine with The termination of signaling by a neurotransmitter in the brain normally requires its re-uptake and metabolism. D-Serine signaling is thought to involve its release from cells to

show abstract

Section: Discussionmentioning

confidence: 81%

Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity

Foltyn

Bendikov

Miranda

et al. 2005

Journal of Biological Chemistry

201

196

View full text Add to dashboard Cite

show abstract

“…We concluded from our results that filtered D-serine is able to enter the pars recta cells across their apical membrane (38,41). The apical uptake carrier has a very low stereospecificity for serine (41) and alanine (10,38) and is, therefore, different from that in the proximal convolution (39). The colocalization of exclusive reabsorption and metabolism of D-serine makes the pars recta the tubule site for recycling the carbon structure of D-amino acids and, at the same time, the target of D-serine nephrotoxicity.…”

mentioning

confidence: 63%

“…In a last set of experiments, we tested whether AIB has an inhibitory effect on D-serine reabsorption in the proximal tubule, thereby preventing D-serine nephrotoxicity. In earlier studies, we characterized D-serine reabsorption in rat kidney in vivo et situ in detail (39,41). We found that D-serine is only reabsorbed in the S 3 segment of the rat proximal tubule by a high-capacity/low-affinity transport system (K m Ϸ 20 mmol/l).…”

Section: Resultsmentioning

confidence: 93%

“…Because D-serine nephrotoxicity is localized in the straight part of the proximal tubule (6,7) and because renal D-serine metabolism by D-amino acid oxidase (D-AAO) is localized there also (8,22,25,44), we have recently investigated (38,41) whether, in contrast to the proximal convolution (39), D-serine is reabsorbed by a specific carrier in the straight part. We concluded from our results that filtered D-serine is able to enter the pars recta cells across their apical membrane (38,41). The apical uptake carrier has a very low stereospecificity for serine (41) and alanine (10,38) and is, therefore, different from that in the proximal convolution (39).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Why isd-serine nephrotoxic and α-aminoisobutyric acid protective?

Krug¹,

Völker²,

Dantzler³

et al. 2007

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

d-Serine selectively causes necrosis of S3 segments of proximal tubules in rats. This leads to aminoaciduria and glucosuria. Coinjection of the nonmetabolizable amino acid α-aminoisobutyric acid (AIB) prevents the tubulopathy. d-serine is selectively reabsorbed in S3, 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 ∼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-[14C]serine or [14C]AIB (0.36 mmol/l) together with [3H]inulin in late proximal tubules in vivo and measured the radioactivity in the final urine. Fractional reabsorption of d-[14C]serine and [14C]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 S3 segments rather than by interfering with intracellular d-AAO-mediated d-serine metabolism.

show abstract

“…In renal, the colocalization of exclusive reabsorption and metabolism of amino acids makes the pars recta the tubule site for the recycling of the carbon structure of D-amino acids [27]. Nonetheless, the great excess of serinuria (12.0±0.2 mg/mL) by normal SD rats ( Table 6) was really astonishing.…”

Section: Discussionmentioning

confidence: 98%

Therapeutic effect of amino acid mixture on type 1 diabetes mellitus with impaired renal methionine reabsorption

Peng¹,

Ker²,

Hsieh³

et al. 2014

J Diab Res Clin Met

View full text Add to dashboard Cite

Background: The main manifestation of Type 1 diabetes mellitus (T1DM) is insulin insufficiency which eventually leads to body weight loss and a diversity of organ dysfunctions. On the other hand, quercetin (QT) is an antioxidant and an insulin secretagogue. We hypothesize that the amino acid mixture (AAM) preparation and/or AAM+ quercetin(QT) probably could ameliorate these adverse effects. Methods: The STZ-DM-Sprague Dawley rat model was carried out and respectively treated with QT, AAM, and AAM+QT. The relevant physiological and biochemical changes in serum and urinary parameters were examined. Results: T1DM exhibited severe insulin insufficiency, body weight loss, increased kidney/body weight ratio, BUN, creatinine clearance, albuminuria and proteinuria, declined serum albumin and amino acid reabsorption involving methionine, leucine and isoleucine. The control showed severe serinuria (12.0±0.2 mg/mL) (p<0.001). AAM caused valinuria (3.6±0.2 mg/mL), argininuria (6.9±0.2 mg/mL) and histidinuria (6.5±0.1 mg/mL) (p<0.05). T1DM rats revealed hyperglycinuria (21.4±0.2 mg/mL) (p<0.01); AAM alleviated hyperglycinuria (13.7±0.2 mg/mL) (p<0.001) but evoked isoleucinuria (8.2±0.2 mg/mL) (p<0.05); QT elicited methioninuria (23.1±0.3 mg/mL) in T1DM and the control (p<0.001); AAM+QT alleviated the methioninuria with extra leucinuria (11.3±0.4 mg/mL) (p<0.05), isoleucinuria (11.4±0.4 mg/mL), tryptophanuria, argininuria and lysinuria (p<0.05). Conclusion: T1DM exhibits severe insulin insufficiency, resulting in severe body weight loss and increased kidney/body weight ratio. T1DM and QT tend to induce methioninineuria. AAM+QT can rescue methioninuria at the expense of leucinuria, isoleucinuria, tryptophanuria, argininuria and lysinuria, implicating the use of AAM with extra supplement of insulin, leucine, isoleucine, tryptophan, arginine and lysine is feasible for alleviation of T1DM.

show abstract

d-Serine is reabsorbed in rat renal pars recta

Cited by 40 publications

References 23 publications

Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity

Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity

Why isd-serine nephrotoxic and α-aminoisobutyric acid protective?

Therapeutic effect of amino acid mixture on type 1 diabetes mellitus with impaired renal methionine reabsorption

Contact Info

Product

Resources

About