Targeting oxidative stress and anti-oxidant defence in diabetic kidney disease
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REVIEW
Targeting oxidative stress and anti‑oxidant defence in diabetic kidney disease Jakob Appel Østergaard1,2,3 · Mark Emmanuel Cooper1 · Karin Agnes Maria Jandeleit‑Dahm1,4 Received: 23 January 2020 / Accepted: 11 May 2020 © Italian Society of Nephrology 2020
Abstract There is an unmet need for new strategies to prevent or postpone the development of diabetic kidney disease. The pathophysiology of this condition includes as a central mechanism an imbalance between the excessive production of reactive oxygen species (ROS) and inadequate anti-oxidant defense. Reduction of ROS is therefore an interesting therapeutic target that warrants further investigation. Herein, we review the drivers of oxidative stress in diabetic kidney disease including NADPH oxidases, mitochondrial ROS production, xanthine oxidase, cytochrome P450, uncoupled eNOS and lipoxygenase. Secondly, the role of anti-oxidative mechanisms in diabetic kidney disease is discussed including the role of the kelch-like ECH-associated protein 1- nuclear factor erythroid 2-related factor 2, lipoxin, oral anti-oxidants and glutathione peroxidase-1. We will also review data supporting the concept that the beneficial renal effects of anti-diabetic drugs that target the glucagon-like peptide 1 receptor and the sodium glucose transporter 2 are, at least in part, due to their impact on oxidative stress in diabetic kidney disease. In the present article we critically evaluate both preclinical studies with cell culture experiments and animal models of diabetic kidney disease as well as covering the current findings from clinical studies addressing targeted interventions towards these pathways. Keywords Diabetic nephropathy · Oxidative stress · Reactive oxygen species · Anti-oxidant defence
Introduction Diabetic kidney disease (DKD) develops in up to 40% of diabetes patients despite a clinical focus on risk factor modification including optimising blood pressure and glucose control as well as remaining the most important predictor of mortality in diabetes [1]. Furthermore, diabetes is still the most common cause of end-stage renal disease (ESRD), which requires expensive dialysis or kidney transplantation * Karin Agnes Maria Jandeleit‑Dahm karin.jandeleit‑[email protected] 1
Department of Diabetes, Central Clinical School, Monash University, The Alfred Centre, Level 5, 99 Commercial Road, Melbourne, VIC 3004, Australia
2
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
3
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
4
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes, Research at Heinrich-Heine University, Düsseldorf, Germany
[2]. Thus, there remains an unmet medical need and it is therefore absolutely essential that we continue our pursuit of novel treatment targets as outlined below. DKD results from complex interactions of multiple pathways, which are induced by hyperglycemia and hemodynamic alterations in diabetes ultimately cau
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