AIMS/HYPOTHESIS: Obesity and hypertension, known pro-inflammatory states, are identified determinants for increased retinal microvascular abnormalities. However, the molecular link between inflammation and microvascular degeneration remains elusive. Thioredoxin-interacting protein (TXNIP) is recognised as an activator of the NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome. This study aims to examine TXNIP expression and elucidate its role in endothelial inflammasome activation and retinal lesions. METHODS: Spontaneously hypertensive (SHR) and control Wistar (W) rats were compared with groups fed a high-fat diet (HFD) (W+F and SHR+F) for 8-10 weeks. RESULTS: Compared with W controls, HFD alone or in combination with hypertension significantly induced formation of acellular capillaries, a hallmark of retinal ischaemic lesions. These effects were accompanied by significant increases in lipid peroxidation, nitrotyrosine and expression of TXNIP, nuclear factor κB, TNF-α and IL-1β. HFD significantly increased interaction of TXNIP-NLRP3 and expression of cleaved caspase-1 and cleaved IL-1β. Immunolocalisation studies identified TXNIP expression within astrocytes and Müller cells surrounding retinal endothelial cells. To model HFD in vitro, human retinal endothelial (HRE) cells were stimulated with 400 μmol/l palmitate coupled to BSA (Pal-BSA). Pal-BSA triggered expression of TXNIP and its interaction with NLRP3, resulting in activation of caspase-1 and IL-1β in HRE cells. Silencing Txnip expression in HRE cells abolished Pal-BSA-mediated cleaved IL-1β release into medium and cell death, evident by decreases in cleaved caspase-3 expression and the proportion of live to dead cells. CONCLUSIONS/ INTERPRETATION: These findings provide the first evidence for enhanced TXNIP expression in hypertension and HFD-induced retinal oxidative/inflammatory response and suggest that TXNIP is required for HFD-mediated activation of the NLRP3 inflammasome and the release of IL-1β in endothelial cells.
AIMS/HYPOTHESIS: Obesity and hypertension, known pro-inflammatory states, are identified determinants for increased retinal microvascular abnormalities. However, the molecular link between inflammation and microvascular degeneration remains elusive. Thioredoxin-interacting protein (TXNIP) is recognised as an activator of the NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome. This study aims to examine TXNIP expression and elucidate its role in endothelial inflammasome activation and retinal lesions. METHODS: Spontaneously hypertensive (SHR) and control Wistar (W) rats were compared with groups fed a high-fat diet (HFD) (W+F and SHR+F) for 8-10 weeks. RESULTS: Compared with W controls, HFD alone or in combination with hypertension significantly induced formation of acellular capillaries, a hallmark of retinal ischaemic lesions. These effects were accompanied by significant increases in lipid peroxidation, nitrotyrosine and expression of TXNIP, nuclear factor κB, TNF-α and IL-1β. HFD significantly increased interaction of TXNIP-NLRP3 and expression of cleaved caspase-1 and cleaved IL-1β. Immunolocalisation studies identified TXNIP expression within astrocytes and Müller cells surrounding retinal endothelial cells. To model HFD in vitro, human retinal endothelial (HRE) cells were stimulated with 400 μmol/l palmitate coupled to BSA (Pal-BSA). Pal-BSA triggered expression of TXNIP and its interaction with NLRP3, resulting in activation of caspase-1 and IL-1β in HRE cells. Silencing Txnip expression in HRE cells abolished Pal-BSA-mediated cleaved IL-1β release into medium and cell death, evident by decreases in cleaved caspase-3 expression and the proportion of live to dead cells. CONCLUSIONS/ INTERPRETATION: These findings provide the first evidence for enhanced TXNIP expression in hypertension and HFD-induced retinal oxidative/inflammatory response and suggest that TXNIP is required for HFD-mediated activation of the NLRP3 inflammasome and the release of IL-1β in endothelial cells.
Authors: Tatiana Helfenstein; Francisco A Fonseca; Sílvia S Ihara; Juliana M Bottós; Flávio T Moreira; Henrique Pott; Michel E Farah; Maria C Martins; Maria C Izar Journal: Int J Exp Pathol Date: 2011-02 Impact factor: 1.925
Authors: Rinke Stienstra; Janna A van Diepen; Cees J Tack; Md Hasan Zaki; Frank L van de Veerdonk; Deshani Perera; Geoffrey A Neale; Guido J Hooiveld; Anneke Hijmans; Irene Vroegrijk; Sjoerd van den Berg; Johannes Romijn; Patrick C N Rensen; Leo A B Joosten; Mihai G Netea; Thirumala-Devi Kanneganti Journal: Proc Natl Acad Sci U S A Date: 2011-08-29 Impact factor: 11.205
Authors: Tien Yin Wong; Bruce B Duncan; Sherita Hill Golden; Ronald Klein; David J Couper; Barbara E K Klein; Larry D Hubbard; A Richey Sharrett; Maria I Schmidt Journal: Invest Ophthalmol Vis Sci Date: 2004-09 Impact factor: 4.799
Authors: R Kawasaki; J M Tielsch; J J Wang; T Y Wong; P Mitchell; Y Tano; M Tominaga; T Oizumi; M Daimon; T Kato; S Kawata; T Kayama; H Yamashita Journal: Br J Ophthalmol Date: 2007-10-26 Impact factor: 4.638
Authors: P Christian Schulze; Jun Yoshioka; Tomosaburo Takahashi; Zhiheng He; George L King; Richard T Lee Journal: J Biol Chem Date: 2004-05-05 Impact factor: 5.157
Authors: Albert E Towers; Maci L Oelschlager; Jay Patel; Stephen J Gainey; Robert H McCusker; Gregory G Freund Journal: Metabolism Date: 2017-03-09 Impact factor: 8.694
Authors: Tauheed Ishrat; Islam N Mohamed; Bindu Pillai; Sahar Soliman; Abdelrahman Y Fouda; Adviye Ergul; Azza B El-Remessy; Susan C Fagan Journal: Mol Neurobiol Date: 2014-06-18 Impact factor: 5.590
Authors: Pavlina Tsoka; Paulo R Barbisan; Keiko Kataoka; Xiaohong Nancy Chen; Bo Tian; Peggy Bouzika; Joan W Miller; Eleftherios I Paschalis; Demetrios G Vavvas Journal: Exp Eye Res Date: 2019-01-29 Impact factor: 3.467