Overlapping roles of NADPH oxidase 4 for diabetic and gadolinium-based contrast agent-induced systemic fibrosis

• Published in: American journal of physiology. Renal physiology 2021-04, Vol.320 (4), p.F617-F627
• Main Authors: Bruno, Francesca, DeAguero, Joshua, Do, Catherine, Lee, Doug Yoon, Tan, Chunyan, Escobar, G Patricia, Wagner, Brent
• Format: Article
• Language: English
• Subjects: Animals; Bile; Contrast agents; Contrast media; Contrast Media - adverse effects; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - chemically induced; Fibrosis; Fibrosis - chemically induced; Fibrosis - pathology; Gadolinium; Gadolinium - adverse effects; Kidney - drug effects; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Magnetic resonance imaging; Mice; NAD(P)H oxidase; NADPH Oxidase 4 - drug effects; NADPH Oxidase 4 - metabolism; Nephrogenic Fibrosing Dermopathy - chemically induced; Nephrogenic Fibrosing Dermopathy - pathology; NOX4 protein; Reactive oxygen species; Renal Insufficiency - chemically induced; Renal Insufficiency - pathology; Risk factors; Streptozocin
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/AJPRENAL.00456.2020

Dozens of millions of people are exposed to gadolinium-based contrast agents annually for enhanced magnetic resonance imaging. Gadolinium-based contrast agents are known nephrotoxins and can trigger the potentially fatal condition of systemic fibrosis. Risk factors are practically entirely undefined. We examined the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Age- and weight-matched mice were randomized to experimental diabetes (streptozotocin) and control groups followed by systemic gadolinium-based contrast agent treatment. Nox4-deficient mice were randomized to experimental diabetes and gadolinium-based contrast agent treatment. Skin fibrosis and cellular infiltration were apparent in both gadolinium-based contrast agent-treated and experimental diabetes groups. Similarly, both groups demonstrated renal pathologies with evidence of reactive oxygen species generation. Deletion of Nox4 abrogated both skin and renal pathology, whether from diabetes or gadolinium-based contrast agent treatment. These discoveries demonstrate the importance of Nox4 in gadolinium-based contrast agent- and diabetes-induced fibrosis. A mouse model of gadolinium-based contrast agent- and diabetes-induced fibrosis was used to demonstrate the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Using these models, we established the role of Nox4 as a mediator of reactive oxygen species generation and subsequent skin and kidney fibrosis. These novel findings have defined Nox-4-mediated mechanisms by which gadolinium-based contrast agents induce systemic diseases.