title: Arginase-2 mediates diabetic renal injury.
abstract: OBJECTIVE
  To determine 1) whether renal arginase activity or expression is increased in diabetes and 2) whether arginase plays a role in development of diabetic nephropathy (DN).
  
  
  METHODS
  The impact of arginase activity and expression on renal damage was evaluated in spontaneously diabetic Ins2(Akita) mice and in streptozotocin (STZ)-induced diabetic Dilute Brown Agouti (DBA) and arginase-2-deficient mice (Arg2(-/-)).
  
  
  RESULTS
  Pharmacological blockade or genetic deficiency of arginase-2 conferred kidney protection in Ins2(Akita) mice or STZ-induced diabetic renal injury. Blocking arginases using S-(2-boronoethyl)-L-cysteine for 9 weeks in Ins2(Akita) mice or 6 weeks in STZ-induced diabetic DBA mice significantly attenuated albuminuria, the increase in blood urea nitrogen, histopathological changes, and kidney macrophage recruitment compared with vehicle-treated Ins2(Akita) mice. Furthermore, kidney arginase-2 expression increased in Ins2(Akita) mice compared with control. In contrast, arginase-1 expression was undetectable in kidneys under normal or diabetes conditions. Arg2(-/-) mice mimicked arginase blockade by reducing albuminuria after 6 and 18 weeks of STZ-induced diabetes. In wild-type mice, kidney arginase activity increased significantly after 6 and 18 weeks of STZ-induced diabetes but remained very low in STZ-diabetic Arg2(-/-) mice. The increase in kidney arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2(-/-) mice.
  
  
  CONCLUSIONS
  These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.forename: Ting
authors.initials: T
authors.lastname: Gao
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Diane
authors.initials: D
authors.lastname: Kepka-Lenhart
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006644:Histiocytes / Q000187:drug effects / Q000473:pathology; D006943:Hyperglycemia / Q000209:etiology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow; D013311:Streptozocin / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013311:Streptozocin; C481673:Arg2 protein, mouse; D001119:Arginase