title: Arginase inhibition mediates renal tissue protection in diabetic nephropathy by a nitric oxide synthase 3-dependent mechanism.
abstract: Recently, we showed that pharmacological blockade or genetic deficiency of arginase-2 confers kidney protection in diabetic mouse models. Here, we tested whether the protective effect of arginase inhibition is nitric oxide synthase 3 (eNOS) dependent in diabetic nephropathy. Experiments were conducted in eNOS-knockout and their wild-type littermate mice using multiple low doses of vehicle or streptozotocin, and treated with continuous subcutaneous infusion of vehicle or the arginase inhibitor S-(2-boronoethyl)-L-cysteine by an osmotic pump. Inhibition of arginases for 6 weeks in diabetic wild-type mice significantly attenuated albuminuria, the increase in plasma creatinine and blood urea nitrogen, histopathological changes, kidney fibronectin and TNF-α expression, kidney macrophage recruitment, and oxidative stress compared with vehicle-treated diabetic wild-type mice. Arginase inhibition in diabetic eNOS-knockout mice failed to affect any of these parameters, but reduced kidney macrophage recruitment and kidney TNF-α expression compared with vehicle-treated diabetic eNOS-knockout mice. Furthermore, diabetic wild-type and eNOS-knockout mice exhibited increased kidney arginase-2 protein, arginase activity, and ornithine levels. Thus, arginase inhibition mediates renal tissue protection in diabetic nephropathy by an eNOS-dependent mechanism and has an eNOS-independent effect on kidney macrophage recruitment.
authors.affiliation: Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Hanning
authors.initials: H
authors.lastname: You
authors.forename: Ting
authors.initials: T
authors.lastname: Gao
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
mesh_terms: D000419:Albuminuria / Q000201:enzymology / Q000517:prevention & control; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D055104:Infusions, Subcutaneous; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009952:Ornithine / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D013311:Streptozocin; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C425062:(2-boronoethyl)-cysteine; D015415:Biomarkers; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D005353:Fibronectins; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D003404:Creatinine; D009952:Ornithine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C481673:Arg2 protein, mouse; D001119:Arginase