Blockade of the N-methyl-D-aspartate glutamate receptor ameliorates lipopolysaccharide-induced renal insufficiency

Chian Shiung Lin, Shun Fa Hung, Ho Shiang Huang, Ming Chieh Ma

研究成果: Article

16 引文 (Scopus)

摘要

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.

原文English
文章編號e0132204
期刊PloS one
10
發行號7
DOIs
出版狀態Published - 2015 七月 2

指紋

Glutamate Receptors
N-Methylaspartate
aspartic acid
N-Methyl-D-Aspartate Receptors
lipopolysaccharides
Renal Insufficiency
Lipopolysaccharides
kidneys
receptors
serine
Kidney
Rats
interleukin-1
Serine
Dizocilpine Maleate
Cells
Interleukin-1
Up-Regulation
rats
cytokines

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

引用此文

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Blockade of the N-methyl-D-aspartate glutamate receptor ameliorates lipopolysaccharide-induced renal insufficiency. / Lin, Chian Shiung; Hung, Shun Fa; Huang, Ho Shiang; Ma, Ming Chieh.

於: PloS one, 卷 10, 編號 7, e0132204, 02.07.2015.

研究成果: Article

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