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Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D


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Lindblom, RS, Higgins, GC, Nguyen, T-V, Arnstein, M, Henstridge, DC ORCID: 0000-0003-4988-767X, Granata, C, Snelson, M, Thallas-Bonke, V, Cooper, ME, Forbes, JM and Coughlan, MT 2020 , 'Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D' , Clinical Science, vol. 134, no. 2 , pp. 239-259 , doi: 10.1042/CS20190787.

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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.

Item Type: Article
Authors/Creators:Lindblom, RS and Higgins, GC and Nguyen, T-V and Arnstein, M and Henstridge, DC and Granata, C and Snelson, M and Thallas-Bonke, V and Cooper, ME and Forbes, JM and Coughlan, MT
Keywords: ell death, cyclophilin D, diabetic nephropathy, mitochondria, mitochondrial permeability transition pores
Journal or Publication Title: Clinical Science
Publisher: Portland Press
ISSN: 0143-5221
DOI / ID Number: 10.1042/CS20190787
Copyright Information:

© 2020 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License 4.0 (CC BY-NC-ND).

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