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139708 - Delineating a role for the mitochondrial permeability.pdf (7.98 MB)

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

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posted on 2023-05-20, 15:40 authored by Lindblom, RSJ, Higgins, GC, Nguyen, T-V, Arnstein, M, Darren HenstridgeDarren Henstridge, Granata, C, Snelson, M, Thallas-Bonke, V, Cooper, ME, Forbes, JM, Coughlan, MT
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.

History

Publication title

Clinical Science

Volume

134

Pagination

239-259

ISSN

0143-5221

Department/School

School of Health Sciences

Publisher

Portland Press

Place of publication

59 Portland Place, London, England, W1N 3Aj

Rights statement

© 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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Expanding knowledge in the biological sciences

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