Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D
| Autor: | Maryann Arnstein, Melinda T. Coughlan, Cesare Granata, Runa S.J. Lindblom, Josephine M. Forbes, Mark E. Cooper, Darren C. Henstridge, Matthew Snelson, Vicki Thallas-Bonke, Tuong-Vi Nguyen, Gavin C Higgins |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Mitochondrion Kidney Mitochondrial Membrane Transport Proteins Diabetes Mellitus Experimental Diabetic nephropathy chemistry.chemical_compound Internal medicine medicine Albuminuria Animals Diabetic Nephropathies Mice Knockout Alisporivir Mitochondrial Permeability Transition Pore Chemistry MPTP Glomerulosclerosis Hydrogen Peroxide General Medicine medicine.disease Streptozotocin Mitochondria Mice Inbred C57BL Proton-Translocating ATPases Endocrinology Mitochondrial permeability transition pore Cyclosporine Kidney Diseases medicine.symptom Cyclophilin D medicine.drug |
| Zdroj: | Clinical Science. 134:239-259 |
| ISSN: | 1470-8736 0143-5221 |
| Popis: | Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif−/−) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif−/− mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif−/− as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes. |
| Databáze: | OpenAIRE |
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