N-methyl-d-aspartate (NMDA) receptors are expressed throughout the kidney and the abundance of these receptors and some of their endogenous agonists is increased in diabetes. Moreover, sustained activation of podocyte NMDA receptors induces Ca2+ influx, oxidative stress, loss of slit diaphragm proteins, and apoptosis. Here we observed that NMDA receptor subunits and their transcripts are increased in podocytes and mesangial cells cultured in elevated glucose compared to controls. A similar increase in NMDA subunits, especially NR1, NR2A and NR2C, was observed in glomeruli and tubules of Akita mice. Sustained continuous treatment with the strong NMDA receptor antagonist dizocilpine (MK-801) for 28 days starting at 8 weeks of age reduced 24-hr albumin excretion, mesangial matrix expansion, and improved glomerular ultrastructure in Akita mice. MK-801 did not alleviate reduced body weight of Akita mice and had no effect on kidney histology or ultrastructure in DBA/2J controls. The structurally dissimilar NMDA antagonist memantine also reduced diabetic nephropathy, although it was less effective than MK-801. Inhibition of NMDA receptors may represent a valid therapeutic approach to reduce renal complications of diabetes, and it is possible to develop well-tolerated agents with minimal CNS effects. Two such agents, memantine and dextromethorphan, are already in widespread clinical use.
- Received February 10, 2016.
- Accepted July 4, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.