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Published online before print October 1, 2009
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Mediate High Glucose-Induced Thioredoxin-Interacting Protein


From the Department of Medicine,* St. Vincents 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.
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