| First Author | Papu John AS | Year | 2019 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 317 |
| Issue | 2 | Pages | E269-E283 |
| PubMed ID | 31039005 | Mgi Jnum | J:281221 |
| Mgi Id | MGI:6357273 | Doi | 10.1152/ajpendo.00251.2018 |
| Citation | Papu John AS, et al. (2019) Hydrogen sulfide inhibits Ca(2+)-induced mitochondrial permeability transition pore opening in type-1 diabetes. Am J Physiol Endocrinol Metab 317(2):E269-E283 |
| abstractText | 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 Ca(2+) permeability, H2S 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 of whether NMDA-R1 mediates Ca(2+) influx causing CypD activation and MPTP opening leading to oxidative stress and renal injury in diabetes. We also tested whether H2S treatment blocks Ca(2+) 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 Ca(2+) permeability, which was ameliorated by H2S treatment. We observed cytosolic Ca(2+) 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 Ca(2+) 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 Ca(2+) permeability through NMDA-R1 pathway. |
