In:
Journal of Molecular Endocrinology, Bioscientifica, Vol. 68, No. 2 ( 2022-02-01), p. 125-136
Abstract:
The pro-inflammatory cytokines secreted by Müller cells aggregate retinal cell loss and vascularization in diabetic retinopathy (DR). The deubiquitinase BRCA1–BRCA2-containing complex subunit 3 (BRCC3)-mediated nucleotide-binding domain and leucine-rich repeat receptor containing a pyrin domain 3 (NLRP3) inflammasome activation participate in this progress. This study aims to clarify whether the E3 ubiquitin ligase synoviolin (SYVN1) relieves DR via regulating the BRCC3/NLRP3 axis. The DR model was established using streptozotocin-induced mice. Immunofluorescence staining with anti-CD31, anti-glutamine synthetase, and anti-vimentin was performed to identify DR and Müller cells. Levels of pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, IL-6, and IL-18, in murine serum and Müller cell supernatants were determined. Co-immunoprecipitation (Co-IP) and ubiquitination assays were used to clarify the interactions among SYVN1, BRCC3, and NLRP3. SYVN1 was reduced and BRCC3 was increased in DR retina and high glucose (HG)-induced Müller cells. Overexpressing 1 promoted the ubiquitination and degradation of BRCC3 and reduced the secretion of proinflammatory cytokines in HG-induced Müller cells. The simultaneous overexpression of 1 and Brcc3 restored the reduction of pro-inflammatory cytokines caused by the overexpression of 1 alone. Co-IP experiments confirmed the interaction between BRCC3 and NLRP3. SYVN1-mediated BRCC3 downregulation promoted NLRP3 ubiquitination and reduced pro-inflammatory cytokine secretion. 1 overexpression reduced retinal vascularization and inflammatory cytokine secretion in DR mice. SYVN1 has a protective effect on DR, whose molecular mechanisms are partly through SYVN1-mediated ubiquitination of BRCC3 and the subsequent downregulation of NLRP3.
Type of Medium:
Online Resource
ISSN:
0952-5041
,
1479-6813
Language:
Unknown
Publisher:
Bioscientifica
Publication Date:
2022
detail.hit.zdb_id:
1478171-2
