Purchase this article with an account.
Jacob R. Russell, Susanne Mohr; Induction of TXNIP (Thioredoxin-Interacting Protein) and Caspase-1 Is Differentially Regulated by Elevated Levels of Various Sugars. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5419.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Diabetes and galactosemia, both induce caspase-1 activation and subsequent IL-1beta production in retinas of diabetic and galactosemic mice leading to retinopathy. We have previously shown that Müller cells are a source for active caspase-1 when exposed to hyperglycemia. Whether elevated levels of other sugars, such as galactose or fructose, can induce caspase-1 in similar fashion has not been tested so far. Moreover, how caspase-1 is activated in these cells by increased sugar levels is unknown to date. Recent studies have suggested that TXNIP (Thioredoxin-Interacting Protein), a known glucose response protein, might be involved in the activation of caspase-1. Therefore, this study was focused on identifying whether sugars like glucose, galactose, and fructose in general can activate the TXNIP pathway and whether the activation of the TXNIP pathway is crucial for caspase-1 activation in retinal Müller cells.
Human retinal Müller cells (hMC) or rat retinal Müller cell line (rMC-1) were treated with medium containing either 5mM glucose, 25mM glucose, 25mM galactose, or 25 mM fructose for 24 hours. Caspase-1 activity was determined using a specific caspase-1 fluorescence substrate (YVAD-AFC). Western blot analysis was used to determine TXNIP expression. RNA levels were examined using RT-PCR.
Galactose significantly increased caspase-1 activity from 359.96 ± 71.5 AFC pmol/mg/min to 615.12 ± 207.96 AFC pmol/mg/min starting at 12 hours in Müller cells. Caspase-1 activity remained increased up to 72 hours compared to control. Activation of caspase-1 by elevated galactose levels was comparable to the effect of high glucose treatment as previously shown. Interestingly, despite being considered a glucose response protein, both galactose and glucose induced TXNIP protein expression by 1.8 ± 0.82 and 1.4 ± 0.63, respectively, in Müller cells at 24 hours. Induction of TXNIP message started at 4 hours and continued to increase up to 24 hours. In contrast, fructose did neither induce TXNIP expression nor caspase-1 activity.
Glucose and galactose but not fructose activate the TXNIP pathway potentially leading to caspase-1 activation in retinal Müller cells indicating that metabolism of these sugars might regulate the TXNIP/caspase-1 pathway. Further studies need to identify the consequence of the activation of the TXNIP pathway to the development of diabetic retinopathy.
This PDF is available to Subscribers Only