Hydrogen sulfide inhibits Ca-induced mitochondrial permeability transition pore opening in type-1 diabetes.

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