Hydrogen Sulfide Inhibits Ca2+‐induced M itochondrial Permeability Transition Pore Opening in Type‐1 Diabetes

Abstract

Hydrogen sulfide (H2S) attenuates N‐Methyl‐D‐Aspartate receptor (NMDA‐R) and mitigates diabetic renal damage but the molecular mechanism is not known. While NMDA‐R 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 that NMDA‐R mediates Ca2+ influx causing CyPD activation and mPTP opening leading to oxidative stress and diabetic renal injury. H2S treatment blocks Ca2+ channel and thus inhibits CyPD and mPTP opening and reduces renal damage. C57BL/6J and Akita (C57BL/6J‐Ins2Akita) mice were treated without or with H2S donor (GYY4137, 0.25mg/Kg/day) intra‐peritoneally for 4 weeks. In vitro studies were performed using mouse glomerular endothelial cells. 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 hyperglycemia along with mt‐CyPD activation, increased mPTP opening and oxidative outburst which were reversed after H2S treatment. Renal injury biomarker, KIM‐1 was up regulated in diabetes and decreased after H2S treatment. Inhibition of NMDA‐R 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. We provide further evidence that H2S protects diabetic kidney by blocking mitochondrial Ca2+ permeability through NMDA‐R1 pathway.