title: l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  l-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA ; Department of Anesthesiology and Perioperative Medicine, Georgia Regents University , Augusta, GA , USA ; Vascular Biology Center, Georgia Regents University , Augusta, GA , USA.
authors.forename: Maritza J
authors.initials: MJ
authors.lastname: Romero
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yao
authors.affiliation: Vascular Biology Center, Georgia Regents University , Augusta, GA , USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Bhatta
authors.affiliation: Vascular Biology Center, Georgia Regents University , Augusta, GA , USA.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Dou
authors.affiliation: Vascular Biology Center, Georgia Regents University , Augusta, GA , USA ; Department of Medicine, Georgia Regents University , Augusta, GA , USA.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
authors.affiliation: Department of Physiology, Georgia Regents University , Augusta, GA , USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Brands
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA ; Department of Medicine, Georgia Regents University , Augusta, GA , USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
authors.affiliation: Vascular Biology Center, Georgia Regents University , Augusta, GA , USA ; Department of Cell Biology and Anatomy, Georgia Regents University , Augusta, GA , USA ; Department of Ophthalmology, Georgia Regents University , Augusta, GA , USA ; VA Medical Center, Georgia Regents University , Augusta, GA , USA.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.affiliation: Intellectual and Developmental Disabilities Research Center/Neuropsychiatric Institute (IDDRC/NPI), University of California Los Angeles School of Medicine , Los Angeles, CA , USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Cederbaum
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Georgia Regents University , Augusta, GA , USA.
authors.forename: C Alvin
authors.initials: CA
authors.lastname: Head
authors.affiliation: Vascular Biology Center, Georgia Regents University , Augusta, GA , USA.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA ; Vascular Biology Center, Georgia Regents University , Augusta, GA , USA ; Division of Pulmonary Medicine, Georgia Regents University , Augusta, GA , USA.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA ; Department of Physiology, Georgia Regents University , Augusta, GA , USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Caldwell
keywords: IL-10; arginase; diabetic nephropathy; glomerulosclerosis; l-citrulline