title: NMDA Receptors as Potential Therapeutic Targets in Diabetic Nephropathy: Increased Renal NMDA Receptor Subunit Expression in Akita Mice and Reduced Nephropathy Following Sustained Treatment With Memantine or MK-801.
abstract: N-methyl-d-aspartate (NMDA) receptors are expressed throughout the kidney, and the abundance of these receptors and some of their endogenous agonists are increased in diabetes. Moreover, sustained activation of podocyte NMDA receptors induces Ca(2+) influx, oxidative stress, loss of slit diaphragm proteins, and apoptosis. We observed that NMDA receptor subunits and their transcripts are increased in podocytes and mesangial cells cultured in elevated glucose compared with 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-h albumin excretion and mesangial matrix expansion and improved glomerular ultrastructure in Akita mice. MK-801 did not alleviate reduced Akita mouse body weight 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 central nervous system effects. Two such agents, memantine and dextromethorphan, are already in widespread clinical use.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX.
authors.forename: Hila
authors.initials: H
authors.lastname: Roshanravan
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX Division of Nephrology, Baylor College of Medicine, Houston, TX sdryer@uh.edu.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Dryer
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003928:Diabetic Nephropathies; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008559:Memantine / Q000627:therapeutic use*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C432823:NR2C NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D008559:Memantine