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

Inflammation is associated with retinal diseases. Our recent data demonstrate that immunoproteasome catalytic subunit beta 2i contributes to angiotensin II (Ang II)-induced retinopathy in mice. Here, we investigated the role of another catalytic subunit beta 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, beta 5i-knockout (KO) mice, or WT mice injected with either adenovirus-expressing beta 5i (Ad-beta 5i) or angiotensin II type 1 receptor (AT1R)-associated protein (Ad-ATRAP), which inhibits AT1R. The beta 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 beta 5i-KO mice but aggravated in Ad-beta 5i-injected mice. Accordingly, beta 5i KO markedly restored Ang II-induced downregulation of ATRAP and activation of AT1R downstream mediators, which was further enhanced in Ad-b5i-injected mice. Interestingly, overexpression of ATRAP significantly abrogated Ang II-induced retinopathy in Ad-beta 5i-injected mice. This study found that beta 5i promoted Ang II-induced retinopathy by promoting ATRAP degradation and activation of AT1R-mediated signals.