Publication

L-citrulline protects from kidney damage in type 1 diabetic mice

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Last modified
  • 02/20/2025
Type of Material
Authors
    Maritza J. Romero, Georgia Regents UniversityLin Yao, Georgia Regents UniversitySupriya Sridhar, Georgia Regents UniversityAnil Bhatta, Georgia Regents UniversityHuijuan Dou, Georgia Regents UniversityGanesan Ramesh, Georgia Regents UniversityMichael W. Brands, Georgia Regents UniversityDavid M. Pollock, Georgia Regents UniversityRuth B. Caldwell, Georgia Regents UniversityStephen D. Cederbaum, University of California Los AngelesClarence Head, Emory UniversityZsolt Bagi, Georgia Regents UniversityRudolf Lucas, Georgia Regents UniversityRobert W. Caldwell, Georgia Regents University
Language
  • English
Date
  • 2013-01-01
Publisher
  • Frontiers Media
Publication Version
Copyright Statement
  • © 2013 Romero, Yao, Sridhar, Bhatta, Dou, Ramesh, Brands, Pollock, Caldwell, Cederbaum, Head, Bagi, Lucas and Caldwell.
License
Final Published Version (URL)
Title of Journal or Parent Work
ISSN
  • 1664-3224
Volume
  • 4
Start Page
  • 480
End Page
  • 480
Grant/Funding Information
  • This work was supported by the Juvenile Diabetes Research Foundation (Innovative grant 5-2009-468 to Maritza J. Romero), the National Institutes of Health National Heart, Lung, and Blood Institute (R01 HL70215 to Robert W. Caldwell and R01 HL104126 to Zsolt Bagi) and the National Institute of Diabetes and Digestive and Kidney Diseases (R24 DK094765 to Rudolf Lucas and Robert W. Caldwell).
Abstract
  • RATIONALE: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of l-arginine (l-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. l-Citrulline (l-cit) supplementation not only increases l-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of l-arg, in the vasculature. AIMS: To investigate whether l-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. METHODS: STZ-C57BL6 mice received l-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and l-cit-treated STZ-rats were evaluated. RESULTS: l-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, l-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. l-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, l-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells. CONCLUSION: l-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.
Author Notes
  • Correspondence: Maritza J. Romero, Departments of Pharmacology and Toxicology and Anesthesiology and Perioperative Medicine, Vascular Biology Center, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912-2300, USA e-mail: mromerolucas@gru.edu
Keywords
Research Categories
  • Health Sciences, Toxicology
  • Health Sciences, General
  • Health Sciences, Pharmacology

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