Chapter II. Diabetic Nephropathy
| Rev Diabet Stud,
2015,
12(1-2):134-156 |
DOI 10.1900/RDS.2015.12.134 |
Targeting Mitochondria and Reactive Oxygen Species-Driven Pathogenesis in Diabetic Nephropathy
Runa Lindblom1,2,3,4, Gavin Higgins1,2,45,, Melinda Coughlan1,2,3,6,7, Judy B. de Haan2,78,
1Glycation, Nutrition and Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
2Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
3Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia
4Equal contribution by first authors
5Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
6Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
7Equal contribution by senior authors
8Oxidative Stress Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
Address correspondence to: Judy B. de Haan, Head, Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia, e-mail: judy.dehaan@bakeridi.edu.au
Manuscript submitted March 30, 2015; accepted April 15, 2015.
Keywords: diabetic nephropathy, reactive oxygen species, apoptosis, necrosis, mitochondrial dysfunction
Abstract
Diabetic kidney disease is one of the major microvascular complications of both type 1 and type 2 diabetes mellitus. Approximately 30% of patients with diabetes experience renal complications. Current clinical therapies can only mitigate the symptoms and delay the progression to end-stage renal disease, but not prevent or reverse it. Oxidative stress is an important player in the pathogenesis of diabetic nephropathy. The activity of reactive oxygen and nitrogen species (ROS/NS), which are by-products of the diabetic milieu, has been found to correlate with pathological changes observed in the diabetic kidney. However, many clinical studies have failed to establish that antioxidant therapy is renoprotective. The discovery that increased ROS/NS activity is linked to mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, cellular senescence, and cell death calls for a refined approach to antioxidant therapy. It is becoming clear that mitochondria play a key role in the generation of ROS/NS and their consequences on the cellular pathways involved in apoptotic cell death in the diabetic kidney. Oxidative stress has also been associated with necrosis via induction of mitochondrial permeability transition. This review highlights the importance of mitochondria in regulating redox balance, modulating cellular responses to oxidative stress, and influencing cell death pathways in diabetic kidney disease. ROS/NS-mediated cellular dysfunction corresponds with progressive disease in the diabetic kidney, and consequently represents an important clinical target. Based on this consideration, this review also examines current therapeutic interventions to prevent ROS/NS-derived injury in the diabetic kidney. These interventions, mainly aimed at reducing or preventing mitochondrial-generated oxidative stress, improving mitochondrial antioxidant defense, and maintaining mitochondrial integrity, may deliver alternative approaches to halt or prevent diabetic kidney disease.
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