N-methyl-d-aspartate receptor hyperfunction contributes to d-serine-mediated renal insufficiency

Area of Science:

• Nephrology
• Neuroscience
• Cellular Biology

Background:

• Glutamate N-methyl-D-aspartate receptors (NMDARs) are implicated in acute renal failure.
• D-serine acts as an NMDAR coagonist, but its role in kidney toxicity is not fully understood.

Purpose of the Study:

• To investigate the role of NMDARs in d-serine-induced nephrotoxicity.
• To elucidate the molecular mechanisms underlying d-serine-mediated renal injury.

Main Methods:

• Utilized LLC-PK1 cells as a proximal tubule model to assess d-serine cytotoxicity.
• Administered d-serine and NMDAR blockers (MK-801, AP-5) to rats to evaluate renal function and damage.
• Measured oxidative stress markers, including superoxide and H2O2 production.
• Investigated the involvement of NADPH oxidase (NOX) and protein kinase C (PKC) signaling pathways.

Main Results:

• D-serine induced dose-dependent cytotoxicity in LLC-PK1 cells, which was blocked by NMDAR inhibitors.
• D-serine treatment in rats led to glucosuria, proteinuria, and tubular damage, which were ameliorated by MK-801.
• NMDAR blockade reduced oxidative stress by inhibiting NOX activity and downregulating NOX4 expression.
• PKC activation was identified as a downstream mediator of NMDAR-induced NOX activation.

Conclusions:

• NMDAR hyperfunction is a key driver of d-serine-induced renal injury.
• The d-serine-NMDAR pathway triggers oxidative stress through the PKC-NOX4 signaling cascade.
• NMDAR blockade represents a potential therapeutic strategy to prevent d-serine-mediated acute kidney injury.