Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to
angiotensin converting enzyme inhibition but no combined synergy in diabetes.
Authors Ward MS, Flemming NB, Gallo LA, Fotheringham AK, McCarthy DA, Zhuang A, Tang PH,
Borg DJ, Shaw H, Harvie B, Briskey DR, Roberts LA, Plan MR, Murphy MP, Hodson
MP, Forbes JM
Submitted By Josephine Forbes on 1/16/2018
Status Published
Journal Scientific reports
Year 2017
Date Published 11/1/2017
Volume : Pages 7 : 15190
PubMed Reference 29123192
Abstract 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.