Epigenetic regulation of TXNIP-mediated oxidative stress and NLRP3 inflammasome activation contributes to SAHH inhibition-aggravated diabetic nephropathy

Abstract

S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. Increased plasma SAH levels were associated with disturbed renal function in patients with diabetes. However, the role and mechanism of SAHH in diabetic nephropathy is still unknown. In the present study, we found that inhibition of SAHH by using its inhibitor adenosine dialdehyde (ADA) accumulates intracellular or plasma SAH levels and increases high glucose-induced podocyte injury and aggravates STZ-induced diabetic nephropathy, which is associated with Nod-like receptor protein 3 (NLRP3) inflammasome activation. Inhibition or knockout of NLRP3 attenuates SAHH inhibition-aggravated podocyte injury and diabetic nephropathy. Additionally, SAHH inhibition increases thioredoxin-interacting protein (TXNIP)-mediated oxidative stress and NLRP3 inflammasome activation, but these effects were not observed in TXNIP knockout mice. Mechanistically, SAHH inhibition increased TXNIP by inhibiting histone methyltransferase enhancer of zeste homolog 2 (EZH2) and reduced trimethylation of histone H3 lysine 27 and its enrichment at promoter of early growth response 1 (EGR1). Moreover, EGR1 is activated and enriched at promoters of TXNIP by SAHH inhibition and is essential for SAHH inhibition-induced TXNIP expression. Inhibition of EGR1 protected against SAHH inhibition-induced NLRP3 inflammasome activation and oxidative stress and diabetic nephropathy. Finally, the harmful effects of SAHH inhibition on inflammation and oxidative stress and diabetic nephropathy were also observed in heterozygote SAHH knockout mice. These findings suggest that EZH2/EGR1/TXNIP/NLRP3 signaling cascade contributes to SAHH inhibition-aggravated diabetic nephropathy. Our study firstly provides a novel insight into the role and mechanism of SAHH inhibition in diabetic nephropathy.

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

“…One is the activation of the NF-κb pathway which promotes the synthesis of NLRP3 protein and IL-1β precursor protein, the other is to trigger the assembly of the inflammasome, such as the production of ROS or TXNIP [ 18 ]. TXNIP is a key regulatory protein that boosts oxidative stress and has recently been identified as an NLRP3 binding protein that activates the NLRP3 inflammasome [ 50 , 51 ]. Our previous investigation, by co-immunoprecipitation, disclosed that TXNIP engages in NLRP3 activation after CVST [ 52 ].…”

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

“…TXNIP is a regulator of oxidative stress [13] and has been studied in many diseases such as pancreatic cancer [12,36], but how ERS regulates oxidative stress in AP is still unknown. A previous study demonstrated that TXNIP is regulated by p-IRE1α in hepatocytes [37].…”

“…TXNIP inhibits the antioxidant activity of thioredoxin by binding to the protein [7]. TXNIP has been widely studied in other diseases, for example, Bechard et al found that TXNIP improved pancreatic cancer due to the inhibition of metastasis [12], Zhang et al found that TXNIP alleviated diabetes by exacerbating oxidative stress [13]. In addition, TXNIP is related to reactive oxygen species (ROS) bursts in cells.…”

Knowledge Domain and Emerging Trends in Podocyte Injury Research From 1994 to 2021: A Bibliometric and Visualized Analysis

“…Notably, inflammation is an important bridge to podocyte injury studies. It often mediates podocyte injury together with autophagy and oxidative stress ( Hou Y. et al, 2020 ; Dai et al, 2021 ).…”