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Whereas NMDA-R1 facilitates Ca<jats:sup>2+<\/jats:sup>permeability, H<jats:sub>2<\/jats:sub>S is known to inhibit L-type Ca<jats:sup>2+<\/jats:sup>channel. High Ca<jats:sup>2+<\/jats:sup>activates cyclophilin D (CypD), a gatekeeper protein of mitochondrial permeability transition pore (MPTP), thus facilitating molecular exchange between matrix and cytoplasm causing oxidative outburst and cell death. We tested the hypothesis of whether NMDA-R1 mediates Ca<jats:sup>2+<\/jats:sup>influx causing CypD activation and MPTP opening leading to oxidative stress and renal injury in diabetes. We also tested whether H<jats:sub>2<\/jats:sub>S treatment blocks Ca<jats:sup>2+<\/jats:sup>channel and thus inhibits CypD and MPTP opening to prevent renal damage. C57BL\/6J and Akita (C57BL\/6J-Ins2<jats:sup>Akita<\/jats:sup>) mice were treated without or with H<jats:sub>2<\/jats:sub>S donor GYY4137 (0.25 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>ip) for 8 wk. In vitro studies were performed using mouse glomerular endothelial cells. Results indicated that low levels of H<jats:sub>2<\/jats:sub>S and increased expression of NMDA-R1 in diabetes induced Ca<jats:sup>2+<\/jats:sup>permeability, which was ameliorated by H<jats:sub>2<\/jats:sub>S treatment. We observed cytosolic Ca<jats:sup>2+<\/jats:sup>influx in hyperglycemic (HG) condition along with mitochondrial-CypD activation, increased MPTP opening, and oxidative outburst, which were mitigated with H<jats:sub>2<\/jats:sub>S treatment. Renal injury biomarker KIM-1 was upregulated in HG conditions and normalized following H<jats:sub>2<\/jats:sub>S treatment. Inhibition of NMDA-R1 by pharmacological blocker MK-801 revealed similar results. We conclude that NMDA-R1-mediated Ca<jats:sup>2+<\/jats:sup>influx in diabetes induces MPTP opening via CypD activation leading to increased oxidative stress and renal injury, and H<jats:sub>2<\/jats:sub>S protects diabetic kidney from injury by blocking mitochondrial Ca<jats:sup>2+<\/jats:sup>permeability through NMDA-R1 pathway.<\/jats:p>","DOI":"10.1152\/ajpendo.00251.2018","type":"journal-article","created":{"date-parts":[[2019,4,30]],"date-time":"2019-04-30T19:54:18Z","timestamp":1556654058000},"page":"E269-E283","source":"Crossref","is-referenced-by-count":35,"title":["Hydrogen sulfide inhibits Ca<sup>2+<\/sup>-induced mitochondrial permeability transition pore opening in type-1 diabetes"],"prefix":"10.1152","volume":"317","author":[{"given":"A. 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