ODP251 Thioredoxin-Interacting Protein (Txnip) And Cellular Senescence: Potential Adverse Effects of Txnip Deficiency.

Abstract

Abstract Thioredoxin-interacting protein (TXNIP) is a ubiquitously expressed protein that belongs to the α-arrestin family of proteins but is unique in that it interacts with and inhibits the function of the endogenous antioxidant, Thioredoxin (Trx). TXNIP is strongly upregulated by hyperglycemia and is associated with increased oxidative stress and promotes pancreatic beta cell apoptosis accelerating the progression of diabetes. Age-dependent dysregulation of the Trx/TXNIP redox system has been implicated in cellular senescence and aging. However, the mechanisms are not fully understood. While Trx overexpression has been reported to protect against aging and age-related diseases, and we found that TXNIP-/- (KO) mice were protected from Diabetic kidney disease, paradoxically, others reported TXNIP KO mice had reduced survival in response to paraquat mediated oxidative stress. To investigate the potential effects of TXNIP in cellular senescence we used primary mouse renal glomerular mesangial cells (MC) from WT and TXNIP KO mice. Passaging of cells leads to replicative senescence. In WT MC this was associated with a significant reduction in TXNIP expression in late passage (LP-passage 25) compared to early passage (EP-passage 5-7) (p<0. 05), and this was accompanied by appearance of the senescence phenotype determined by significant increases in expression of the cellular senescence markers, p53, p16, p21, phosphorylation of histone H2AX (p<0. 05) and senescence associated beta-galactosidase staining (13-fold increase) (p<0. 01). To determine whether TXNIP downregulation played a causal role, primary MC from TXNIP KO were compared to WT at EP 5. TXNIP KO showed significantly higher expression of senescence markers P53 and P16 (p<0. 05), and beta-galactosidase staining (15-fold). AKT activation has been implicated in replicative senescence. Here, increased phosphorylation of AKT and its substrate FOXO were found in LP versus EP WT, and EP KO versus WT MC (p<0. 05). These studies indicate that TXNIP downregulation is a mediator of replicative senescence associated with increased AKT signaling. Thus, while beneficial for diabetes, targeting TXNIP may have long term untoward effects on aging. Presentation: No date and time listed