Published online before print October 1, 2009

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(American Journal of Pathology. 2009;175:1858-1867.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090263

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

Weier Qi^*, Xinming Chen, John Holian, Christina Y.R. Tan^*, Darren J. Kelly^* and Carol A. Pollock

From the Department of Medicine,^* St. Vincent’s Hospital, University of Melbourne, Melbourne, Australia; and Kolling Institute, Department of Medicine, Royal North Shore Hospital and University of Sydney, Sydney, Australia

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