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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Albuminuria / enzymology
-
Albuminuria / prevention & control
-
Animals
-
Arginase / antagonists & inhibitors*
-
Arginase / metabolism
-
Biomarkers / blood
-
Blood Urea Nitrogen
-
Boronic Acids / administration & dosage
-
Boronic Acids / pharmacology*
-
Creatinine / blood
-
Diabetes Mellitus, Experimental / blood
-
Diabetes Mellitus, Experimental / chemically induced
-
Diabetes Mellitus, Experimental / complications
-
Diabetes Mellitus, Experimental / drug therapy*
-
Diabetes Mellitus, Experimental / enzymology
-
Diabetic Nephropathies / blood
-
Diabetic Nephropathies / enzymology
-
Diabetic Nephropathies / etiology
-
Diabetic Nephropathies / prevention & control*
-
Enzyme Inhibitors / administration & dosage
-
Enzyme Inhibitors / pharmacology*
-
Fibronectins / metabolism
-
Infusions, Subcutaneous
-
Kidney / drug effects*
-
Kidney / enzymology
-
Macrophages / drug effects
-
Macrophages / metabolism
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Nitric Oxide Synthase Type III / deficiency
-
Nitric Oxide Synthase Type III / genetics
-
Nitric Oxide Synthase Type III / metabolism*
-
Ornithine / metabolism
-
Oxidative Stress / drug effects
-
Streptozocin
-
Time Factors
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
(2-boronoethyl)-cysteine
-
Biomarkers
-
Boronic Acids
-
Enzyme Inhibitors
-
Fibronectins
-
Tumor Necrosis Factor-alpha
-
Streptozocin
-
Creatinine
-
Ornithine
-
Nitric Oxide Synthase Type III
-
Nos3 protein, mouse
-
Arg2 protein, mouse
-
Arginase