Hydrogen Sulfide Inhibits Ca 2+ ‐induced M itochondrial Permeability Transition Pore Opening in Type‐1 Diabetes

Hydrogen sulfide (H 2 S) attenuates N‐Methyl‐D‐Aspartate receptor (NMDA‐R) and mitigates diabetic renal damage but the molecular mechanism is not known. While NMDA‐R facilitates Ca 2+ permeability, H 2 S is known to inhibit L‐type Ca 2+ channel. High Ca 2+ 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 that NMDA‐R mediates Ca 2+ influx causing CyPD activation and mPTP opening leading to oxidative stress and diabetic renal injury. H 2 S treatment blocks Ca 2+ channel and thus inhibits CyPD and mPTP opening and reduces renal damage. C57BL/6J and Akita (C57BL/6J‐Ins2 Akita ) mice were treated without or with H 2 S donor (GYY4137, 0.25mg/Kg/day) intra‐peritoneally for 4 weeks. In vitro studies were performed using mouse glomerular endothelial cells. Low levels of H 2 S and increased expression of NMDA‐R1 in diabetes induced Ca 2+ permeability, which was ameliorated by H 2 S treatment. We observed cytosolic Ca 2+ influx in hyperglycemia along with mt‐CyPD activation, increased mPTP opening and oxidative outburst which were reversed after H 2 S treatment. Renal injury biomarker, KIM‐1 was up regulated in diabetes and decreased after H 2 S treatment. Inhibition of NMDA‐R by pharmacological blocker, MK‐801 revealed similar results. We conclude that NMDA‐R1 mediated Ca 2+ influx in diabetes induces mPTP opening via CyPD activation leading to increased oxidative stress and renal injury. We provide further evidence that H 2 S protects diabetic kidney by blocking mitochondrial Ca 2+ permeability through NMDA‐R1 pathway.