TXNIP与内质网应激和糖尿病肾病密切相关。我们在NHMC和Sur1-E1506K+/+糖尿病小鼠中，证实高糖通过修饰组蛋白乙酰化调控TXNIP表达。我们进而在组蛋白去乙酰化酶SIRT1敲除小鼠发现：高脂喂养后的野生型小鼠的肾脏系膜基质增加和TXNIP表达升高可被Exenatide逆转；在SIRT1+/-小鼠上述表现无显著改善。即SIRT1介导Exenatide降低小鼠肾脏TXNIP表达和改善肾脏基质沉积效应；但机制未明。SIRT1参与调控多种转录因子活性。我们在前期发现高糖诱导SIRT1、ERS通路转录因子XBP1和TXNIP表达的变化，提示三者存在相互作用。本研究旨在获得SIRT1与XBP1直接相互作用的可靠证据，阐明SIRT1修饰XBP1乙酰化对TXNIP表达的调控这一事件在Exenatide肾脏保护作用中的机制，为确立SIRT1作为糖尿病肾病治疗的新靶点提供充分的科学依据。

Histone acetylation might be taken into account in the role of glucose in diabetic kidney disease. Thioredoxin-interacting protein (TXNIP) has been shown to play an important role in endoplasmic reticulum stress (ERS) and the pathogenesis of DKD. We tested whether glucose by epigenetic mechanisms could induce expression of TXNIP in normal human mesangial cell line (NHMC) and a diabetes mouse model (Sur1-E1506K +/+). In kidneys from Sur1-E1506K+/+ mice, hyperglycemia-induced TXNIP expression was associated with stimulation of activating histone marks H3K9ac at the promoter region of the gene. Glucose also exerted coordinated changes in histone marks and TXNIP gene expression in mesangial cells. We confirmed the involvement of histone acetylation in glucose-stimulated TXNIP expression by reversing or enhancing acetylation using histone acetyltransferase p300 inhibitor C646 and the histone deacetylase inhibitor trichostatin A. We then tested further in a SIRT1 (an NAD+-dependent protein deacetylase) knockout mice. After 8 weeks of exenatide treatment in male SIRT1+/- mice challenged with a high-fat diet and their wild-type littermates, we found that matrix deposition and TXNIP expression increased in the kidney, which were improved dramatically in the WT group, but diminished in SIRT1+/- mice. A coordinated change in XBP1, transcriptional factor involved in the ERS pathway, could be found too. Based on these finding, we speculated that SIRT1 mediates the effect of exenatide on ameliorating TXNIP expression and DKD. Further studies would be performed to examine the modification of histone acetylation by SIRT1 to the development of glucose induced XBP1, and the increased proinflammatory gene TXNIP expression, thereby predisposing to DKD. It is promising to give strong evidence that SIRT1 could be a therapeutic target of DKD.