title: Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation.
abstract: Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3-dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate L-arginine. Lack of L-arginine results in reduced NO production and eNOS uncoupling, which lead to endothelial dysfunction. Therefore, we hypothesized that L-arginine or L-citrulline supplementation would ameliorate diabetic nephropathy. DBA mice injected with multiple low doses of vehicle or streptozotocin (50 mg/kg ip for 5 days) were provided drinking water with or without L-arginine (1.5%, 6.05 g·kg(-1)·day(-1)) or L-citrulline (1.66%, 5.73 g·kg(-1)·day(-1)) for 9 wk. Nonsupplemented diabetic mice showed significant increases in albuminuria, blood urea nitrogen, glomerular histopathological changes, kidney macrophage recruitment, kidney TNF-α and fibronectin mRNA expression, kidney arginase activity, kidney arginase-2 protein expression, and urinary oxidative stress along with a significant reduction of nephrin and eNOS protein expression and kidney nitrite + nitrate compared with normal mice after 9 wk of diabetes. Surprisingly, L-arginine or L-citrulline supplementation in diabetic mice did not affect any of these parameters despite greatly increasing kidney and plasma arginine levels. These findings demonstrate that chronic L-arginine or L-citrulline supplementation does not prevent or reduce renal injury in a model of type 1 diabetes.
authors.affiliation: Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania;
authors.forename: Hanning
authors.initials: H
authors.lastname: You
authors.affiliation: Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania;
authors.forename: Ting
authors.initials: T
authors.lastname: Gao
authors.affiliation: Department of Comparative Medicine, Penn State University College of Medicine, Hershey, Pennsylvania; and.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.affiliation: Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania; asa17@psu.edu.
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
mesh_terms: D000596:Amino Acids / Q000097:blood / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000097:blood / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D002956:Citrulline / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D019587:Dietary Supplements; D005353:Fibronectins / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D009566:Nitrates / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000596:Amino Acids; D005353:Fibronectins; D008565:Membrane Proteins; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C113267:nephrin; D002956:Citrulline; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D001119:Arginase
keywords: diabetic nephropathy; l-arginine; l-citrulline; oral supplementation