Nephrotoxic Action of D-Serine Determined by Renal Enzyme Excretion in Rats

Raab, W.; Hohenegger, M; Kaiser, E

doi:10.1159/000136004

Cited by 6 publications

(2 citation statements)

References 7 publications

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“…This suggestion is supported by the de novo synthesis and release of D-serine by cultured tubular cells during LPS-mediated tubular cell damage ( Fig 5 ). Since D-serine acts as an endogenous ligand for the NMDA receptor, and NR1 is present in renal tubules [ 1 , 8 ], we speculate that D-serine-induced nephrotoxicity may be the result of NMDA receptor over-stimulation, as demonstrated by previous studies [ 31 – 35 ]. Whether the D-serine-mediated effects on NMDA receptor function influence nephrotoxicity warrants further study.…”

Section: Discussionmentioning

confidence: 83%

“…High plasma levels of D-serine are nephrotoxic because D-serine can be reabsorbed by straight segments of the proximal tubules, which causes tubular cell necrosis [ 31 – 34 ]. D-serine taken up by tubular cells is metabolized by an intracellular enzyme, D-amino acid oxidase, which generates reactive oxygen species via the depletion of reduced glutathione, thereby contributing to tubular damage [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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Blockade of the N-Methyl-D-Aspartate Glutamate Receptor Ameliorates Lipopolysaccharide-Induced Renal Insufficiency

et al. 2015

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N-methyl-D-aspartate (NMDA) receptor activation in rat kidney reduces renal perfusion and ultrafiltration. Hypoperfusion-induced ischemia is the most frequent cause of functional insufficiency in the endotoxemic kidney. Here, we used non-hypotensive rat model of lipopolysaccharide-induced endotoxemia to examine whether NMDA receptor hyperfunction contributes to acute kidney injury. Lipopolysaccharide-induced renal damage via increased enzymuria and hemodynamic impairments were ameliorated by co-treatment with the NMDA receptor blocker, MK-801. The NMDA receptor NR1 subunit in the rat kidney mainly co-localized with serine racemase, an enzyme responsible for synthesizing the NMDA receptor co-agonist, D-serine. The NMDA receptor hyperfunction in lipopolysaccharide-treated kidneys was demonstrated by NR1 and serine racemase upregulation, particularly in renal tubules, and by increased D-serine levels. Lipopolysaccharide also induced cell damage in cultured tubular cell lines and primary rat proximal tubular cells. This damage was mitigated by MK-801 and by small interfering RNA targeting NR1. Lipopolysaccharide increased cytokine release in tubular cell lines via toll-like receptor 4. The release of interleukin-1β from these cells are the most abundant. An interleukin-1 receptor antagonist not only attenuated cell death but also abolished lipopolysaccharide-induced NR1 and serine racemase upregulation and increases in D-serine secretion, suggesting that interleukin-1β-mediated NMDA receptor hyperfunction participates in lipopolysaccharide-induced tubular damage. The results of this study indicate NMDA receptor hyperfunction via cytokine effect participates in lipopolysaccharide-induced renal insufficiency. Blockade of NMDA receptors may represent a promising therapeutic strategy for the treatment of sepsis-associated renal failure.

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