Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney

Abstract

Diabetic kidney disease is the leading cause of end-stage renal disease. Genetic factors have been suggested to contribute to its susceptibility. However, results from genetic studies are disappointing possibly because the role of glucose in diabetic kidney disease predisposed by epigenetic mechanisms has not been taken into account. Since thioredoxin-interacting protein (TXNIP) has been shown to play an important role in the pathogenesis of diabetic kidney disease, we tested whether glucose could induce expression of TXNIP in the kidney by epigenetic mechanisms. In kidneys from diabetic Sur1-E1506K(+/+) mice, hyperglycemia-induced Txnip expression was associated with stimulation of activating histone marks H3K9ac, H3K4me3, and H3K4me1, as well as decrease in the repressive histone mark H3K27me3 at the promoter region of the gene. Glucose also coordinated changes in histone marks and TXNIP gene expression in mouse SV40 MES13 mesangial cells and the normal human mesangial cell line NHMC. The involvement of histone acetylation in glucose-stimulated TXNIP expression was confirmed by reversing or enhancing acetylation using the histone acetyltransferase p300 inhibitor C646 or the histone deacetylase inhibitor trichostatin A. Thus, glucose is a potent inducer of histone modifications, which could drive expression of proinflammatory genes and thereby predispose to diabetic kidney disease.

Emerging roles of the myocardin family of proteins in lipid and glucose metabolism

“…; Zhong & Kowluru, ; De Marinis et al . ). One of the hallmarks of diabetic nephropathy and of a variety of chronic kidney diseases is the accelerated synthesis of extracellular matrix leading to tubulointerstitial fibrosis.…”

Histone acetylation of glucose-induced thioredoxin-interacting protein gene expression in pancreatic islets

“…Although it is not clear if HAT gene expression and activity is affected by diabetes state in pancreatic islets, previous studies in other tissues have shown that HAT activity and histone acetylation is increased in kidneys of diabetic mice (Wang et al, 2015;Cai et al, 2016;De Marinis et al, 2016), as well as increased p300 gene expression in diabetic rat heart (Aziz et al, 2013). Inhibition of p300 by chemical inhibitor curcumin has been shown to prevent renal damage and dysfunction in streptozotocin (STZ)-induced diabetic mice (Wang et al, 2015).…”

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

“…More recently, novel curcumin analogs and derivatives have been identified for their potential use as anti-diabetic agents (i.e., for kidney disease). In particular, the curcumin analog C66 has been shown to mitigate diabetic nephropathy in diabetic mice through the suppression of c-Jun N-terminal kinase (JNK) activation, p300/CBP expression and total HAT activity (96). In another study examining the epigenetic effects of glucose on the expression of the proinflammatory gene, thioredoxininteracting protein (TXNIP), in diabetic Sur1-E1506K +/+ mice, it was discovered that the p300 inhibitor C646 reverses histone acetylation and consequently, represses hyperglycemiastimulated TXNIP expression (97) (Figure 3B).…”