Hydrogen sulfide mitigates diabetic nephropathy through NMDA receptor mediated renal remodeling

Abstract

Diabetic nephropathy is a leading cause of vascular morbidity and mortality. Recently, the involvement of N‐methyl‐D‐aspartate receptor (NMDAR) and hydrogen sulfide (H2S) in diabetes associated complications has been implicated. Our aim in this study was to determine whether H2S mitigates diabetic nephropathy by modulating gap junction and matrix proteins by antagonizing NMDAR. We used a diabetic model (Akita, C57BL/6J‐Ins1Akita), matrix metalloproteinase‐9 knockout (KO) [(MMP‐9−/−)] and double KO of Akita/MMP‐9−/− mice and in vitro cell culture.ResultsDiabetic kidneys showed decreased levels of H2S and its enzymes CBS and CSE in both mRNA and protein level and increased expression of NMDA‐R1, connexin‐40, ‐43 (Cx‐40,‐43) and MMP‐9. Treatment with H2S reversed these effects. In double KO mice, NMDA‐R1 was high but Cx‐40, ‐43 was normal. Additionally, treatment with NMDA‐R1 blocker dizicilpine (MK801) failed to disrupt connexin. Glomerular endothelial cells treated with high glucose indicated dysregulated Cx‐40, ‐43. Inhibition of NMDA‐R1 by MK801, silencing MMP‐9 by siRNA or H2S treatment preserved gap junction proteins. We conclude that in diabetic nephropathy, remodeling is mediated by NMDA‐R1 associated MMP‐9 activation and H2S plays a significant role in mitigating nephropathy.