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Diabetes‐induced arginase activity contributes to vascular and renal fibrosis and dysfunction
Author(s) -
Romero Maritza Josefina,
Iddings Jennifer,
Platt Daniel,
Caldwell Ruth B.,
Caldwell Robert W.
Publication year - 2008
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.22.2_supplement.643
Subject(s) - arginase , medicine , endocrinology , fibrosis , diabetes mellitus , vasodilation , ornithine , nitric oxide , arginine , chemistry , biochemistry , amino acid
Impaired endothelial cell dependent (ECD) vasodilation and vascular fibrosis (VF) are prominent complications in diabetes. We previously reported that increased arginase activity in diabetic rats competes with NOS for L‐arginine decreasing NO production and ECD vasodilation. Treatment with simvastatin (Sim) or L‐citrulline (L‐cit) prevents these effects. Arginase catabolizes L‐arginine into ornithine and urea. Elevated ornithine leads to increased polyamine and proline production, which are involved in cell growth and collagen deposition. Our present study indicates that increased arginase activity in diabetic rats is associated with coronary VF as preventing arginase activation with Sim blocks these effects. Sim or L‐cit treatment also prevents renal (glomerular and interstitial) fibrosis and proteinuria in diabetic rats. We examined the role of arginase (A) isoforms in AI +/+ /AII −/− or AI +/− /AII −/− knockout (KO) and wild type (WT) mice in diabetes‐induced impairment of ECD vasodilation and VF. Arginase activity is increased by 160% and 120% in aortas of diabetic WT and AI +/+ /AII −/− KO mice respectively, compared to controls. Partial deletion of AI prevents this effect. Moreover, ECD vasodilation was less impaired in the AI +/− /AII −/− KO than in the WT diabetic mice. These results correlate with less VF in AI +/− /AII −/− KO vs WT diabetic mice. Our results suggest that diabetes‐induced increases in arginase I activity are associated with vascular and renal fibrosis. Supported by NIH grant RO1 HL70215.