Transcription factors Krüppel-like factor 6 and peroxisome proliferator-activated receptor-{gamma} 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-gamma (PPAR-gamma) 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-gamma. By using siRNAs and overexpressing constructs, the role of KLF6 and PPAR-gamma 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-gamma agonists. In contrast, reduced expression of KLF6 by siRNA or exposure to PPAR-gamma agonists attenuated high glucose-induced Txnip expression and promoter activity. KLF6-Txnip promoter binding was decreased in KLF6-silenced cells, whereas PPAR-gamma agonists increased PPAR-gamma-Txnip promoter binding. Indeed, silencing of KLF6 increased PPAR-gamma expression, suggesting endogenous regulation of PPAR-gamma expression by KLF6. Moreover, renal KLF6 and Txnip expression increased in rats with diabetes mellitus and was inhibited by PPAR-gamma agonist treatment; however, KLF6 expression did not change in HK-2 cells exposed to PPAR-gamma agonists. Hence, Txnip expression and promoter activity are mediated via divergent effects of KLF6 and PPAR-gamma transcriptional regulation.