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

Abstract

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 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 the 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.

Gadolinium Deposition Disease: A Case Report and the Prevalence of Enhanced MRI Procedures Within the Veterans Health Administration

“…Renal elimination (K P0 ) of Gd is intermediate (> 54 d), and long-term (ie, years) in patients (regardless of renal function). 10,11,26 Some Gdbased contrast agent may remain intact in the tissues years after exposure (similar to a "forever" chemical, harbored intracellularly with ill-defined effects on normal physiology). 46 Some Gd is dechelated from the proprietary pharmaceutical and likely rapidly complexes into compounds that comprise the nanostructures found in patients and in our models.…”

“…These fibroblast precursors express procollagen type I, the activated myofibroblast marker α-SMA stress fibers, Nox4-derived ROS, concomitant with an increase of pro-fibrotic TGF-β, proliferation markers (Ki67), and histologic fibrosis. [3][4][5][6]26 B, Gd-based contrast agents have been known to be injurious to the kidney since approval for use in humans. We have discovered that systemic treatment with Gd-based contrast agents culminates in nanoparticle formation within lysosomal vesicles-evidence that there is dechelation in vivo.…”

“…7,8 Kidney injury may be mediated by the generation of reactive oxygen species from NADPH oxidase 4 (Nox4). 26 Gd retention, Gd-induced multisymptomatic illnesses, Gd-associated plaques, Gd-induced neurotoxicity, and nephrogenic systemic fibrosis are part of a continuum (with Gd as the common thread)-a theme of the September 8, 2017, US Food and Drug Administration (FDA) Medical Imaging Drugs Advisory Committee meeting. 27 Patients, patient advocacy groups, and regulating agencies are concerned about longterm retention of a nonphysiologic rare earth element such as Gd.…”

“…8,26 Graphics courtesy of Brent Wagner. Magnetic Resonance Imaging Procedures With Contrast for Patients With Kidney Disease in the VA a…”

Rare Earth Metallosis: Gadolinium-rich Nanoparticle Formation from Magnetic Resonance Imaging Contrast Agents in Rodent and Human Kidney

“…Our rodent models demonstrated the formation of gadolinium-rich nanoparticles in the kidney and skin following systemic MRI contrast agent treatment [13][14][15][16][17][18][19]. Gadolinium-rich densities have been found in neuronal cytoplasm and nuclei in the brains of individuals exposed to MRI contrast agents during the course of routine care [11].…”