NMDA Receptors Mediates Homocysteine-Induced Sclerotic Action on Rat Mesangial Cells

The N‐methyl D‐aspartate receptors (NMDAr) are a glutamate receptor that has been extensively studied in the central nervous system and is suggested as a homocysteine (Hcys) binding receptor. However, the role of NMDAr in the Hcys‐induced renal glomerular dysfunction or injury is still unknown. The present study determined whether the NMDAr is present in rat mesangial cells (RMCs) and whether these receptors are involved in Hcys‐induced glomerular injury. Real‐time RT‐PCR and Western blot analysis confirmed that NMDAr subunits are present both in RMCs and in rat kidneys. Dizocilpine (MK801), a noncompetitive antagonist of the NMDA receptors, blocked the Hcys‐induced Rac GTPase activation by 46%, which was accompanied by a 66% reduction of Hcys‐induced NADPH oxidase dependent superoxide (O 2 ‐. ) production as measured by Electron Spin Resonance (ESR) spectrometric assay. Correspondingly, MK801 also attenuated Hcys‐increased expression of tissue inhibitor of metalloproteinase‐1 (TIMP‐1) and consequently led to increase in matrix metalloproteinase‐1 (MMP‐1) activity. These results indicate that NMDAr exist in rat mesangial cells and mediate, at least in part, Hcys‐induced enhancement of local oxidative stress and abnormal metabolism of extracellular matrix components in rat mesangial cells (Supported by NIH Grants HL57244, HL75316, DK‐54927 and HL89563).