Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes

Ammar A. Abdelrahman; Porsche V. Sandow; Jing Wang; Zhimin Xu; Modesto Rojas; John S. Bomalaski; Tahira Lemtalsi; Ruth B. Caldwell; Robert W. Caldwell

doi:10.1016/j.molmet.2024.102020

Molecular Metabolism (Nov 2024)

Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes

Ammar A. Abdelrahman,
Porsche V. Sandow,
Jing Wang,
Zhimin Xu,
Modesto Rojas,
John S. Bomalaski,
Tahira Lemtalsi,
Ruth B. Caldwell,
Robert W. Caldwell

Affiliations

Ammar A. Abdelrahman: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912 USA; Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA
Porsche V. Sandow: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912 USA; Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA
Jing Wang: Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA
Zhimin Xu: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA
Modesto Rojas: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912 USA; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA
John S. Bomalaski: Polaris Pharmaceuticals, Inc., San Diego, CA 92121, USA
Tahira Lemtalsi: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA
Ruth B. Caldwell: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA
Robert W. Caldwell: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912 USA; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912 USA; Corresponding author. Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.

DOI: https://doi.org/10.1016/j.molmet.2024.102020
Journal volume & issue: Vol. 89
p. 102020

Abstract

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Objective: Chronic inflammation and oxidative stress mediate the pathological progression of diabetic complications, like diabetic retinopathy (DR), peripheral neuropathy (DPN) and impaired wound healing. Studies have shown that treatment with a stable form of arginase 1 that reduces l-arginine levels and increases ornithine and urea limits retinal injury and improves visual function in DR. We tested the therapeutic efficacy of PEGylated arginine deiminase (ADI-PEG20) that depletes l-arginine and elevates l-citrulline on diabetic complications in the db/db mouse model of type 2 diabetes (T2D). Methods: Mice received intraperitoneal (IP), intramuscular (IM), or intravitreal (IVT) injections of ADI-PEG20 or PEG20 as control. Effects on body weight, fasting blood glucose levels, blood-retinal-barrier (BRB) function, visual acuity, contrast sensitivity, thermal sensitivity, and wound healing were determined. Studies using bone marrow-derived macrophages (BMDM) examined the underlying signaling pathway. Results: Systemic injections of ADI-PEG20 reduced body weight and blood glucose and decreased oxidative stress and inflammation in db/db retinas. These changes were associated with improved BRB and visual function along with thermal sensitivity and wound healing. IVT injections of either ADI-PEG20, anti-VEGF antibody or their combination also improved BRB and visual function. ADI-PEG20 treatment also prevented LPS/IFNℽ-induced activation of BMDM in vitro as did depletion of l-arginine and elevation of l-citrulline. Conclusions/interpretation: ADI-PEG20 treatment limited signs of DR and DPN and enhanced wound healing in db/db mice. Studies using BMDM suggest that the anti-inflammatory effects of ADI-PEG20 involve blockade of the JAK2-STAT1 signaling pathway via l-arginine depletion and l-citrulline production.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.sciencedirect.com/journal/molecular-metabolism

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