Poster Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

MITOCHONDRIAL TARGETING OF SUPEROXIDE BY MITOQ IMPROVES METABOLIC RENAL DYSFUNCTION. (#225)

Micheal S Ward 1 , Nicole B Flemming 1 , Linda A Gallo 1 , Amelia K Fotheringham 1 , Josephine M Forbes 1
  1. Mater Research Institute - University of Queensland, Brisbane, QLD, Australia

Aim: Our objective was to investigate if targeting mitochondrial ROS using a unique anti-oxidant MitoQ could improve renal function in experimental diabetes.

Background: Pathological progression of renal disease (RD) in diabetes is associated with mitochondrial dysfunction attributed in part to excess reactive oxygen species (ROS) generation. Progression of ~30% of diabetic individuals to RD highlights possible underlying susceptibility.

Methods: Groups (n=10/group; 8W of age) of randomised male db/db and db/m mice to (i) Vehicle (H2O), (ii) MitoQ (MQ), (iii) Ramipril (Ram) or (iv) Co-therapy (MQRam) were followed for 12 weeks. Human immortalized podocytes and primary proximal tubular cells (PTC) were also studied using a Seahorse XF24 analyser to define mitochondrial respiratory function after normal (NORM; 5mM glucose & 100pM insulin), diabetic-like (DIA; 15mM & 500pM) and modulating (MOD; 2 hour alternating treatments) conditions in the presence and absence of MQ.

Results: In vivo pharmacological interventions each improved renal function (Sinistrin GFR and UAER) in db/db mice. Oral glucose tolerance testing suggested improvements in renal function with MQ were independent of improved glycaemic control.  Analysis of freshly isolated renal mitochondria showed improved function with MQ treatments.  In vitro, human PTCs had greater maximal respiratory capacity (MRC) and ATP content than podocytes in NORM.  Under DIA, MRC and ATP content were reduced in both cell types, significantly in podocytes. However, mimicking glucose excursions, via MOD, podocytes and PTCs elevated MRC and ATP content, significantly in podocytes, compared with NORM. MQ targeting of podocytes attenuated significant decreases presenting under DIA.

Conclusion: Targeting of mitochondrial ROS by MQ has efficacy in experimental models of type 2 diabetes and mechanistically improves mitochondrial function both in vivo in renal cortical mitochondria and in cultured human cells.