title: The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells.
abstract: Krüppel-like factor 4 (KLF4) is known to mitigate inflammation in several cell types. Using human proximal tubule cells, the present study aimed to investigate the role of KLF4 in regulating transforming growth factor (TGF)-β₁ induced inflammatory and fibrotic responses. Human kidney proximal tubular cells were exposed to high glucose, or TGF-β₁ and KLF4 expressions were determined. Cells were then transfected with empty vector or KLF4 and exposed to 2-ng/mL TGF-β₁ for up to 72 h. Inflammatory proteins (macrophage migration inhibitory factor and monocyte chemoattractant protein-1) and pro-fibrotic proteins (fibronectin and collagen IV) were measured after 72 h by enzyme-linked immunosorbent assay and western blot, respectively. To determine the relevance to in vivo models of chronic kidney disease, KLF4 protein expression in streptozotocin-induced diabetic mice was determined. Krüppel-like factor 4 messenger RNA (mRNA) levels were significantly reduced in high glucose-treated human kidney proximal tubular cells. High glucose increased TGF-β₁ mRNA expression, which significantly increased migration inhibitory factor and monocyte chemoattractant protein-1 protein secretion. Transforming growth factor-β₁ significantly increased fibronectin and collagen IV protein expression. The overexpression of KLF4 significantly reduced TGF-β-mediated increases in migration inhibitory factor and monocyte chemoattractant protein-1 but had no effect on TGF-β-mediated fibronectin and collagen IV mRNA and protein expression. The levels of KLF4 mRNA were significantly reduced in the diabetic kidney, and diabetic animals had a significant reduction in renal tubular expression of KLF4 proteins. This data suggest that KLF4 reduces inflammation induced by TGF-β₁, suggesting a therapeutic role for KLF4 in diabetic nephropathy.
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Ellein
authors.initials: E
authors.lastname: Mreich
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Chen
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Amgad
authors.initials: A
authors.lastname: Zaky
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Saad
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D053773:Transforming Growth Factor beta1 / Q000633:toxicity*
chemical_list: D018836:Inflammation Mediators; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D053773:Transforming Growth Factor beta1
keywords: Krüppel-like factor 4 (KLF4); diabetic nephropathy; fibrosis; inflammation; proximal tubule; transforming growth factor-beta1 (TGF-β1)