Hydrogen sulfide (H₂S) attenuates N-methyl-d-aspartate receptor-R1 (NMDA-R1) and mitigates diabetic renal damage; however, the molecular mechanism is not well known. Whereas NMDA-R1 facilitates Ca²⁺ permeability, H₂S is known to inhibit L-type Ca²⁺ channel. High Ca²⁺ 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 Ca²⁺ influx causing CypD activation and MPTP opening leading to oxidative stress and renal injury in diabetes. We also tested whether H₂S treatment blocks Ca²⁺ channel and thus inhibits CypD and MPTP opening to prevent renal damage. C57BL/6J and Akita (C57BL/6J-Ins2^Akita) mice were treated without or with H₂S donor GYY4137 (0.25 mg·kg^-1·day^-1 ip) for 8 wk. In vitro studies were performed using mouse glomerular endothelial cells. Results indicated that low levels of H₂S and increased expression of NMDA-R1 in diabetes induced Ca²⁺ permeability, which was ameliorated by H₂S treatment. We observed cytosolic Ca²⁺ influx in hyperglycemic (HG) condition along with mitochondrial-CypD activation, increased MPTP opening, and oxidative outburst, which were mitigated with H₂S treatment. Renal injury biomarker KIM-1 was upregulated in HG conditions and normalized following H₂S treatment. Inhibition of NMDA-R1 by pharmacological blocker MK-801 revealed similar results. We conclude that NMDA-R1-mediated Ca²⁺ influx in diabetes induces MPTP opening via CypD activation leading to increased oxidative stress and renal injury, and H₂S protects diabetic kidney from injury by blocking mitochondrial Ca²⁺ permeability through NMDA-R1 pathway.

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