Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes

Micheal S Ward; Nicole B Flemming; Linda A Gallo; Amelia K Fotheringham; Domenica A Mccarthy; Aowen Zhuang; Peter H Tang; Danielle J Borg; Hannah Shaw; Benjamin Harvie; David R Briskey; Llion A Roberts; Manuel R Plan; Michael Murphy; Mark P Hodson; Josephine M Forbes

doi:10.1038/s41598-017-15589-x

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Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes

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Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes

Micheal S Ward, Nicole B Flemming, Linda A Gallo, Amelia K Fotheringham, Domenica A Mccarthy, Aowen Zhuang, Peter H Tang, Danielle J Borg, Hannah Shaw, Benjamin Harvie, …

Scientific Reports, Vol.7, pp.1-14

2017

DOI: https://doi.org/10.1038/s41598-017-15589-x

PMCID: PMC5680236

PMID: 29123192

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Abstract

Angiotensin

Animals

Converting Enzyme Inhibitors

Diabetic Nephropathies

Disease Models

Drug Therapy

Mice

Molecular Targeted Therapy

Organophosphorus Compounds

Ramipril

Ubiquinone

chronic kidney disease

diabetes complications

Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D); (ii) MitoQ (DMitoQ;0.6 mg/kg/day); (iii) Ramipril (DRam;3 mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db/db mice for 12 weeks (n = 11–13/group). Non-diabetic (C) db/m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown.

Details

Title: Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes
Authors: Micheal S Ward (Author) - The University of Queensland
Nicole B Flemming (Author) - The University of Queensland
Linda A Gallo (Author) - The University of Queensland
Amelia K Fotheringham (Author) - The University of Queensland
Domenica A Mccarthy (Author) - The University of Queensland
Aowen Zhuang (Author) - The University of Queensland
Peter H Tang (Author) - University of Cincinnati
Danielle J Borg (Author) - The University of Queensland
Hannah Shaw (Author) - The University of Queensland
Benjamin Harvie (Author) - The University of Queensland
David R Briskey (Author) - The University of Queensland
Llion A Roberts (Author) - The University of Queensland
Manuel R Plan (Author) - The University of Queensland
Michael Murphy (Author) - University of Cambridge
Mark P Hodson (Author) - The University of Queensland
Josephine M Forbes (Author) - The University of Queensland
Publication details: Scientific Reports, Vol.7, pp.1-14
Publisher: Nature Publishing Group
Date published: 2017
DOI: 10.1038/s41598-017-15589-x
ISSN: 2045-2322
PMID: 29123192; PMC5680236
Copyright note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Organisation Unit: School of Health - Biomedicine; University of the Sunshine Coast, Queensland; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99620607102621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Endocrinology & Metabolism

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