title: Arginase inhibition: a new treatment for preventing progression of established diabetic nephropathy.
abstract: Our previous publication showed that inhibition of arginase prevents the development of diabetic nephropathy (DN). However, identification of targets that retard the progression of established DN-which is more clinically relevant-is lacking. Therefore, we tested the hypothesis that arginase inhibition would prevent the progression of established DN. Effects of arginase inhibition were compared with treatment with the angiotensin-converting enzyme inhibitor captopril, a current standard of care in DN. Experiments were conducted in Ins2(Akita) mice treated with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) or captopril starting at 6 wk of age for 12 wk (early treatment) or starting at 12 wk of age for 6 wk (late treatment). Early and late treatment with BEC resulted in protection from DN as indicated by reduced albuminuria, histological changes, kidney macrophage infiltration, urinary thiobarbituric acid-reactive substances, and restored nephrin expression, kidney nitrate/nitrite, kidney endothelial nitric oxide synthase phosphorylation, and renal medullary blood flow compared with vehicle-treated Ins2(Akita) mice at 18 wk of age. Interestingly, early treatment with captopril reduced albuminuria, histological changes, and kidney macrophage infiltration without affecting the other parameters, but late treatment with captopril was ineffective. These findings highlight the importance of arginase inhibition as a new potential therapeutic intervention in both early and late stages of diabetic renal injury.
authors.affiliation: Department of Medicine, Division of Nephrology, Penn State University College of Medicine, Hershey, Pennsylvania;
authors.forename: Hanning
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Medicine, Division of Nephrology, 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: Department of Medicine, Division of Nephrology, Penn State University College of Medicine, Hershey, Pennsylvania; asa17@psu.edu.
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D018450:Disease Progression; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D016896:Treatment Outcome
chemical_list: C425062:(2-boronoethyl)-cysteine; D000806:Angiotensin-Converting Enzyme Inhibitors; D001897:Boronic Acids; D002216:Captopril; D052250:Nitric Oxide Synthase Type III; D001119:Arginase
keywords: ACEi; arginase; established diabetic nephropathy; nitric oxide