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

Autor:	Ward MS; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia., Flemming NB; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.; Schools of Biomedical Sciences, Woolloongabba, Queensland, Australia., Gallo LA; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.; Schools of Biomedical Sciences, Woolloongabba, Queensland, Australia., Fotheringham AK; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.; Schools of Biomedical Sciences, Woolloongabba, Queensland, Australia., McCarthy DA; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia., Zhuang A; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.; Medicine, Schools of Biomedical Sciences, Woolloongabba, Queensland, Australia., Tang PH; Department of Paediatrics, University of Cincinnati, Cincinnati, Ohio, USA., Borg DJ; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.; Schools of Biomedical Sciences, Woolloongabba, Queensland, Australia., Shaw H; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia., Harvie B; The University of Queensland Biological Resources, St Lucia, Queensland, Australia., Briskey DR; Human Movement and Nutrition Sciences, St Lucia, Queensland, Australia., Roberts LA; Human Movement and Nutrition Sciences, St Lucia, Queensland, Australia., Plan MR; Metabolomics Australia Queensland Node, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia., Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Hodson MP; Medicine, Schools of Biomedical Sciences, Woolloongabba, Queensland, Australia.; Pharmacy The University of Queensland, St Lucia, Queensland, Australia.; Metabolomics Australia Queensland Node, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia., Forbes JM; Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia. josephine.forbes@mater.uq.edu.au.; Medicine, Schools of Biomedical Sciences, Woolloongabba, Queensland, Australia. josephine.forbes@mater.uq.edu.au.; Department of Medicine, The University of Melbourne, Heidelberg, Australia. josephine.forbes@mater.uq.edu.au.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2017 Nov 09; Vol. 7 (1), pp. 15190. Date of Electronic Publication: 2017 Nov 09.
DOI:	10.1038/s41598-017-15589-x
Abstrakt:	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.
Databáze:	MEDLINE
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