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Abstract: FR-OR120

Characterizing the Bioenergetic Profile of Kidney Mitochondria in Human Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Coughlan, Melinda T., Monash University, Melbourne, Victoria, Australia
  • Granata, Cesare, Monash University, Melbourne, Victoria, Australia
  • Ekinci, Elif, University of Melbourne, Heidelberg West, Victoria, Australia
  • Laskowski, Adrienne, Alfred Health , Melbourne, New South Wales, Australia
  • Cooper, Mark E., Monash University, Melbourne, Victoria, Australia
  • Wilson, Scott, Alfred Health , Melbourne, New South Wales, Australia

Group or Team Name

  • Glycation, Nutrition and Metabolism Laboratory; Department of Diabetes, Monash University
Background

Optimal mitochondrial respiration is central to renal function. We have shown a decline in mitochondrial respiratory function in the kidney in experimental diabetes prior to development of characteristic kidney lesions. Despite a large body of work focussing on the role of mitochondrial dysfunction in diabetic kidney disease (DKD), the majority of studies have been performed in the kidneys of animal models and no study to date has determined if there is a defect in mitochondrial bioenergetics within the renal cortex of individuals with diabetes.

Methods

Renal cortical tissue was obtained after informed patient consent from the macroscopically/microscopically healthy portion of tumor nephrectomies. Renal cortices were freshly collected from non-diabetic controls (ND, n=15) and patients with diabetes (D, n=12). Oxygen consumption rates were determined with a substrate-uncoupler-inhibitor titration protocol by high resolution respirometry (Oxygraph-2k respirometer, Oroboros Instruments) in saponin-permeabilized tissue. In addition, respiration rates were also measured for a subset of specimens (n=12 ND, n=9 D) in mitochondria isolated by differential centrifugation.

Results

In permeabilized renal cortex, fatty acid-induced mitochondrial respiration was increased in patients with diabetes compared to non-diabetic patients. Coupled maximal mitochondrial respiration with electron input through electron transfer flavoprotein, complex I (CI) and CII was greater in patients with diabetes compared to non-diabetic patients. The uncoupled state of maximal respiration, experimentally induced by FCCP to collapse the proton gradient across the mitochondrial inner membrane and to measure the capacity of the electron transfer system was also increased in the setting of diabetes. Intriguingly, in isolated mitochondria, the opposite was observed in that there was a decrease in mitochondrial respiration in patients with diabetes, using all three protocols, suggesting that per unit mitochondria, there is an overall decline in mitochondrial respiratory function.

Conclusion

Our findings demonstrate for the first time that patients with diabetes display a profile of altered renal mitochondrial respiratory control. Further studies are required to determine defective sites within the mitochondria.

Funding

  • Government Support - Non-U.S.