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Hydrogen sulfide mitigates diabetic nephropathy through NMDA receptor mediated renal remodeling
Author(s) -
Kundu Sourav,
Tyagi Aaron,
Coley Denise,
Sathnur Pushpakumar,
Sen Utpal
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.687.5
Subject(s) - diabetic nephropathy , nmda receptor , diabetes mellitus , medicine , endocrinology , connexin , nephropathy , receptor , chemistry , pharmacology , gap junction , biochemistry , intracellular
Diabetic nephropathy is a leading cause of vascular morbidity and mortality. Recently, the involvement of N‐methyl‐D‐aspartate receptor (NMDAR) and hydrogen sulfide (H 2 S) in diabetes associated complications has been implicated. Our aim in this study was to determine whether H 2 S mitigates diabetic nephropathy by modulating gap junction and matrix proteins by antagonizing NMDAR. We used a diabetic model (Akita, C57BL/6J‐Ins1 Akita ), matrix metalloproteinase‐9 knockout (KO) [(MMP‐9−/−)] and double KO of Akita/MMP‐9−/− mice and in vitro cell culture. Results Diabetic kidneys showed decreased levels of H 2 S 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 H 2 S 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 H 2 S treatment preserved gap junction proteins. We conclude that in diabetic nephropathy, remodeling is mediated by NMDA‐R1 associated MMP‐9 activation and H 2 S plays a significant role in mitigating nephropathy.