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Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D.
- Source :
-
Clinical science (London, England : 1979) [Clin Sci (Lond)] 2020 Jan 31; Vol. 134 (2), pp. 239-259. - Publication Year :
- 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.<br /> (© 2020 The Author(s).)
- Subjects :
- Albuminuria genetics
Albuminuria metabolism
Animals
Peptidyl-Prolyl Isomerase F antagonists & inhibitors
Peptidyl-Prolyl Isomerase F genetics
Cyclosporine pharmacology
Diabetes Mellitus, Experimental genetics
Diabetic Nephropathies genetics
Diabetic Nephropathies metabolism
Hydrogen Peroxide metabolism
Kidney drug effects
Kidney metabolism
Kidney pathology
Kidney Diseases genetics
Mice, Inbred C57BL
Mice, Knockout
Mitochondria drug effects
Mitochondria metabolism
Mitochondrial Membrane Transport Proteins genetics
Mitochondrial Permeability Transition Pore
Proton-Translocating ATPases metabolism
Peptidyl-Prolyl Isomerase F metabolism
Diabetes Mellitus, Experimental metabolism
Kidney Diseases metabolism
Mitochondrial Membrane Transport Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8736
- Volume :
- 134
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical science (London, England : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 31943002
- Full Text :
- https://doi.org/10.1042/CS20190787