Are reactive oxygen species still the basis for diabetic complications?
Despite the wealth of pre-clinical support for a role for reactive oxygen and nitrogen species (ROS/RNS) in the aetiology of diabetic complications, enthusiasm for antioxidant therapeutic approaches has been dampened by less favourable outcomes in large clinical trials. This has necessitated a re-evaluation of pre-clinical evidence and a more rational approach to antioxidant therapy. The present review considers current evidence, from both pre-clinical and clinical studies, to address the benefits of antioxidant therapy. The main focus of the present review is on the effects of direct targeting of ROS-producing enzymes, the bolstering of antioxidant defences and mechanisms to improve nitric oxide availability. Current evidence suggests that a more nuanced approach to antioxidant therapy is more likely to yield positive reductions in end-organ injury, with considerations required for the types of ROS/RNS involved, the timing and dosage of antioxidant therapy, and the selective targeting of cell populations. This is likely to influence future strategies to lessen the burden of diabetic complications such as diabetes-associated atherosclerosis, diabetic nephropathy and diabetic retinopathy.
*Diabetic Nephropathy Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Elyse
E
Di Marco
*Diabetic Nephropathy Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Jay C
JC
Jha
†Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Arpeeta
A
Sharma
§Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia.
Jennifer L
JL
Wilkinson-Berka
*Diabetic Nephropathy Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Karin A
KA
Jandeleit-Dahm
†Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Judy B
JB
de Haan
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001393:Azoles / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015195:Drug Design; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000627:therapeutic use; D006801:Humans; D054833:Isoindoles; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D016566:Organoselenium Compounds / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000975:Antioxidants; D001393:Azoles; D020536:Enzyme Activators; D054833:Isoindoles; D016566:Organoselenium Compounds; D010455:Peptides; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C042986:ebselen; D052250:Nitric Oxide Synthase Type III