title: Blockade of the N-Methyl-D-Aspartate Glutamate Receptor Ameliorates Lipopolysaccharide-Induced Renal Insufficiency.
abstract: 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.
authors.affiliation: Department of Surgery, Liou-Ying Hospital, Chi-Mei Medical Center, Tainan Hsien, Taiwan.
authors.forename: Chian-Shiung
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Department of Urology, Far Eastern Memorial Hospital, New Taipei, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Hung
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Ho-Shiang
authors.initials: HS
authors.lastname: Huang
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Ma
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D019446:Endotoxemia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D053583:Interleukin-1beta / Q000502:physiology; D007677:Kidney Function Tests; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018374:LLC-PK1 Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D019998:Racemases and Epimerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D012694:Serine / Q000032:analysis; D013552:Swine; D051197:Toll-Like Receptor 4 / Q000502:physiology; D000099300:Serine Racemase
chemical_list: D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D051197:Toll-Like Receptor 4; D000099300:Serine Racemase; C409466:NR1 NMDA receptor; C495347:Tlr4 protein, rat; C482199:lipopolysaccharide, E coli O55-B5