Mechanisms of diabetes-induced endothelial cell senescence: Role of arginase 1

Esraa Shosha, Zhimin Xu, S. Priya Narayanan, Tahira Lemtalsi, Abdelrahman Y. Fouda, Modesto Rojas, Ji Xing, David Fulton, R. William Caldwell, Ruth B. Caldwell

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

We have recently found that diabetes-induced premature senescence of retinal endothelial cells is accompanied by NOX2-NADPH oxidase-induced increases in the ureohydrolase enzyme arginase 1 (A1). Here, we used genetic strategies to determine the specific involvement of A1 in diabetes-induced endothelial cell senescence. We used A1 knockout mice and wild type mice that were rendered diabetic with streptozotocin and retinal endothelial cells (ECs) exposed to high glucose or transduced with adenovirus to overexpress A1 for these experiments. ABH [2(S)-Amino-6-boronohexanoic acid] was used to inhibit arginase activity. We used Western blotting, immunolabeling, quantitative PCR, and senescence associated β-galactosidase (SA β-Gal) activity to evaluate senescence. Analyses of retinal tissue extracts from diabetic mice showed significant increases in mRNA expression of the senescence-related proteins p16INK4a, p21, and p53 when compared with non-diabetic mice. SA β-Gal activity and p16INK4a immunoreactivity were also increased in retinal vessels from diabetic mice. A1 gene deletion or pharmacological inhibition protected against the induction of premature senescence. A1 overexpression or high glucose treatment increased SA β-Gal activity in cultured ECs. These results demonstrate that A1 is critically involved in diabetes-induced senescence of retinal ECs. Inhibition of arginase activity may therefore be an effective therapeutic strategy to alleviate diabetic retinopathy by preventing premature senescence.

Original languageEnglish (US)
Article number1215
JournalInternational journal of molecular sciences
Volume19
Issue number4
DOIs
StatePublished - Apr 17 2018

Keywords

  • Arginase
  • Diabetes mellitus
  • Diabetic retinopathy
  • Endothelial cells
  • Hyperglycemia
  • Retina
  • Senescence

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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