Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

We demonstrated recently that thioredoxin-interacting protein (Txnip) and the transcription factor Krüppel-like factor 6 (KLF6) were up-regulated in both in vivo and in vitro models of diabetic nephropathy, thus promoting renal injury. Conversely, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been shown to be renoprotective. Hence, this study was undertaken to determine whether Txnip expression is regulated by the transcription factors KLF6 and PPAR-γ. By using siRNAs and overexpressing constructs, the role of KLF6 and PPAR-γ in Txnip transcriptional regulation was determined in human kidney proximal tubule cells and in streptozocin-induced diabetes mellitus in Sprague-Dawley rats, in vitro and in vivo models of diabetic nephropathy, respectively. KLF6 overexpression increased Txnip expression and promoter activity, which was inhibited by concurrent exposure to PPAR-γ agonists. In contrast, reduced expression of KLF6 by siRNA or exposure to PPAR-γ agonists attenuated high glucose-induced Txnip expression and promoter activity. KLF6-Txnip promoter binding was decreased in KLF6-silenced cells, whereas PPAR-γ agonists increased PPAR-γ-Txnip promoter binding. Indeed, silencing of KLF6 increased PPAR-γ expression, suggesting endogenous regulation of PPAR-γ expression by KLF6. Moreover, renal KLF6 and Txnip expression increased in rats with diabetes mellitus and was inhibited by PPAR-γ agonist treatment; however, KLF6 expression did not change in HK-2 cells exposed to PPAR-γ agonists. Hence, Txnip expression and promoter activity are mediated via divergent effects of KLF6 and PPAR-γ transcriptional regulation.