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Elucidating the Role of Arginases in Diabetic Nephropathy: Arginase 2‐dependent and ‐independent Effects
Author(s) -
Awad Alaa S.,
You Hanning,
Gao Ting,
Cooper Timothy K,
Morris Sidney M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.740.1
Subject(s) - arginase , diabetes mellitus , endocrinology , diabetic nephropathy , medicine , nephropathy , kidney , biology , arginine , biochemistry , amino acid
Diabetes is the leading cause of end stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. As current therapies for progression of diabetic nephropathy are only moderately successful, identification of underlying mechanisms of disease process is essential in order to develop more effective therapies. We showed previously that treatment with an arginase inhibitor or genetic deficiency of the arginase 2 isozyme was protective against several key features of nephropathy in diabetic mouse models. However, those studies did not determine whether all tested markers of diabetic nephropathy were dependent only on arginase 2 expression. The objective of this study was to identify features of diabetic nephropathy that are associated specifically with arginase 2 expression. The arginase inhibitor S‐(2‐boronoethyl)‐L‐cysteine or vehicle was continuously infused via minipump in male wild‐type and arginase 2‐deficient ( Arg2 −/− ) mice for 12 weeks following induction of diabetes by streptozotocin injection. Our results demonstrate that elevated urinary albumin excretion rate and plasma urea levels, and decreased renal medullary blood flow, were associated almost completely and specifically with arginase 2 expression. Furthermore, diabetes‐dependent increases in renal fibronectin mRNA levels were largely dependent on arginase 2 expression, with no indication of any significant contribution by arginase 1. These findings indicate that arginase 2 selectively mediates major aspects of diabetic renal injury. However, increases in renal macrophage infiltration and renal TNF‐α mRNA levels occurred independently of arginase 2 expression but were almost entirely abolished by treatment with the arginase inhibitor, indicating that arginase 1 is required for increases in these markers of diabetic renal pathology. Support or Funding Information This study was supported by NIH Grants DK094930 and DK094930S1