Ablation of Immunoproteasome ?5i Subunit Suppresses Hypertensive Retinopathy by Blocking ATRAP Degradation in Mice.

ABSTRACT: Inflammation is associated with retinal diseases. Our recent data demonstrate that immunoproteasome catalytic subunit ?2i contributes to angiotensin II (Ang II)-induced retinopathy in mice. Here, we investigated the role of another catalytic subunit ?5i 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, ?5i-knockout (KO) mice, or WT mice injected with either adenovirus-expressing ?5i (Ad-?5i) or angiotensin II type 1 receptor (AT1R)-associated protein (Ad-ATRAP), which inhibits AT1R. The ?5i 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 ?5i-KO mice but aggravated in Ad-?5i-injected mice. Accordingly, ?5i KO markedly restored Ang II-induced downregulation of ATRAP and activation of AT1R downstream mediators, which was further enhanced in Ad-?5i-injected mice. Interestingly, overexpression of ATRAP significantly abrogated Ang II-induced retinopathy in Ad-?5i-injected mice. This study found that ?5i promoted Ang II-induced retinopathy by promoting ATRAP degradation and activation of AT1R-mediated signals.

SUBMITTER: Wang S 

PROVIDER: S-EPMC6953897 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature