Ablation of Immunoproteasome β5i Subunit Suppresses Hypertensive Retinopathy by Blocking ATRAP Degradation in Mice

Mol Ther. 2020 Jan 8;28(1):279-292. doi: 10.1016/j.ymthe.2019.09.025. Epub 2019 Oct 5.

Abstract

Inflammation is associated with retinal diseases. Our recent data demonstrate that immunoproteasome catalytic subunit β2i contributes to angiotensin II (Ang II)-induced retinopathy in mice. Here, we investigated the role of another catalytic subunit β5i in regulating retinopathy and its underlying mechanisms. We induced a murine model of retinopathy by infusing Ang II (3,000 ng/kg/min) for 3 weeks into wild-type (WT) mice, β5i-knockout (KO) mice, or WT mice injected with either adenovirus-expressing β5i (Ad-β5i) or angiotensin II type 1 receptor (AT1R)-associated protein (Ad-ATRAP), which inhibits AT1R. The β5i expression and chymotrypsin-like activity were most significantly elevated in Ang II-infused retinas and serum from patients with hypertensive retinopathy. Moreover, Ang II infusion-induced retinopathy was markedly attenuated in β5i-KO mice but aggravated in Ad-β5i-injected mice. Accordingly, β5i KO markedly restored Ang II-induced downregulation of ATRAP and activation of AT1R downstream mediators, which was further enhanced in Ad-β5i-injected mice. Interestingly, overexpression of ATRAP significantly abrogated Ang II-induced retinopathy in Ad-β5i-injected mice. This study found that β5i promoted Ang II-induced retinopathy by promoting ATRAP degradation and activation of AT1R-mediated signals.

Keywords: ATRAP; angiotensin II; immunosubunit β5i; inflammation; oxidative stress; retinopathy; vascular dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adult
  • Aged
  • Angiotensin II / pharmacology
  • Animals
  • Disease Models, Animal
  • Female
  • Gene Knockout Techniques
  • Genetic Vectors
  • Humans
  • Hypertensive Retinopathy / blood*
  • Hypertensive Retinopathy / chemically induced
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Proteasome Endopeptidase Complex / genetics*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Subunits / genetics*
  • Protein Subunits / metabolism*
  • Proteolysis*
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism
  • Signal Transduction / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Agtrap protein, mouse
  • Protein Subunits
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • LMP7 protein
  • Proteasome Endopeptidase Complex