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.
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