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Updated: Dec 20, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Targeting oxidative stress and anti-oxidant defence in diabetic kidney disease
Jakob Appel Østergaard1,2,3, Mark Emmanuel Cooper1, Karin Agnes Maria Jandeleit-Dahm4,5
1Department of Diabetes, Central Clinical School, Monash University, The Alfred Centre, Level 5, 99 Commercial Road, Melbourne, VIC, 3004, Australia.
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.
Insights
Diabetic kidney disease stems from oxidative stress. Targeting reactive oxygen species (ROS) pathways offers a promising therapeutic strategy to protect kidney function in diabetes.
Area of Science:
- Nephrology
- Endocrinology
- Biochemistry
Background:
- Diabetic kidney disease (DKD) presents a significant clinical challenge with limited preventative strategies.
- A central pathological mechanism in DKD is the imbalance between reactive oxygen species (ROS) production and antioxidant defenses.
Purpose of the Study:
- To review the key drivers of oxidative stress in DKD.
- To discuss the role of endogenous and exogenous antioxidant mechanisms in mitigating DKD.
- To evaluate the impact of oxidative stress on the renal benefits of certain anti-diabetic medications.
Main Methods:
- Critical evaluation of preclinical studies (cell culture, animal models) and clinical findings.
- Review of literature on oxidative stress pathways in DKD.
- Analysis of antioxidant defense systems and their modulation.
Main Results:
- Identified key ROS generators in DKD: NADPH oxidases, mitochondrial ROS, xanthine oxidase, cytochrome P450, uncoupled eNOS, and lipoxygenase.
- Highlighted the protective roles of antioxidant mechanisms like Nrf2, lipoxin, and glutathione peroxidase-1.
- Supported the hypothesis that GLP-1 receptor agonists and SGLT2 inhibitors exert renal benefits partly through modulating oxidative stress.
Conclusions:
- Targeting oxidative stress pathways is a viable therapeutic avenue for preventing or delaying DKD.
- Understanding the interplay between ROS, antioxidant defenses, and anti-diabetic drug action is crucial for DKD management.
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ROS generation is regulated and maintained at moderate levels necessary...