title: Role of Kruppel-like factor 6 in transforming growth factor-beta1-induced epithelial-mesenchymal transition of proximal tubule cells.
abstract: Krüppel-like factor 6 (KLF6) is a DNA-binding protein containing a triple zinc-fingered motif and plays a key role in the regulation of cell proliferation, differentiation, and development. More recently it has been implicated in hepatic fibrosis via its binding to the transforming growth factor (TGF)-beta control element. In the kidney, epithelial-mesenchymal transition (EMT) is a major contributor to the pathogenesis of renal fibrosis, with TGF-beta1 being a key mediator of EMT. The present study aimed to determine the role of KLF6 and TGF-beta1 in EMT in proximal tubule cells. To determine the relevance in clinical disease, KLF6 was measured in kidneys of streptozotocin-induced diabetic Ren-2 rats and in cells exposed to high (30 mM) glucose. TGF-beta1 was confirmed to induce EMT by morphological change, loss of E-cadherin, and gain in vimentin expression. KLF6 mRNA expression was concomitantly measured. To determine the role of KLF6 in EMT, the above markers of EMT were determined in KLF6-silenced (small interfering RNA) and KLF6-overexpressing proximal tubule cells. KLF6 overexpression significantly promoted a phenotype consistent with EMT. High glucose induced KLF6 in proximal tubule cells (P < 0.05). This increase in KLF6 in response to high glucose was TGF-beta1 mediated. In an in vivo model of diabetic nephropathy KLF6 increased at week 8 (P < 0.05). KLF6 plays a permissive role in TGF-beta1-induced EMT in proximal tubule cells. Its upregulation in in vivo models of diabetic nephropathy suggests it as a potential therapeutic target.
authors.affiliation: Kolling Institute, Department of Medicine, Royal North Shore Hospital, Sydney.
authors.forename: John
authors.initials: J
authors.lastname: Holian
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ellein
authors.initials: E
authors.lastname: Mreich
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Chen