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.
Qi
Weier
W
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Australia. wqi@medstv.unimelb.edu.au
Chen
Xinming
X
Holian
John
J
Tan
Christina Y R
CY
Kelly
Darren J
DJ
Pollock
Carol A
CA
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C105465:KLF6 protein, human; C491357:Klf6 protein, rat; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C486715:TXNIP protein, human; C493796:TXNIP protein, rat; D005947:Glucose