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Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D
- Source :
- Clinical Science. 134:239-259
- Publication Year :
- 2020
- Publisher :
- Portland Press Ltd., 2020.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 14708736 and 01435221
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- Clinical Science
- Accession number :
- edsair.doi.dedup.....c9d439367927952f4a1fdfe35364abbf