title: Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells.
abstract: Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui, Japan. Electronic address: hkimura@u-fukui.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mikami
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kamiyama
authors.affiliation: Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kasuno
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Division of Nephrology, Obama Municipal Hospital, Obama, Fukui, Japan.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwano
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D055551:HSP27 Heat-Shock Proteins; D047494:PPAR delta; D014409:Tumor Necrosis Factor-alpha; D042582:Vascular Endothelial Growth Factor C; D048051:p38 Mitogen-Activated Protein Kinases; D000077333:Telmisartan
keywords: HSP27; PPAR; TNF-α; Telmisartan; VEGF-C; p38MAPK