title: Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells.
abstract: Telmisartan, an angiotensin II receptor type 1 blocker (ARB), was recently reported to promote lipolysis in mice by acting as a peroxisome proliferator-activated receptor (PPAR)-δ activator, although in clinical studies, it has also been recognized to activate PPAR-γ as a major cause of its pleiotropic actions. The aim of this study was to investigate whether telmisartan activates endogenous PPAR-δ and thereby exerts anti-fibrotic effects in human mesangial cells (HMC). Immunohistochemical analysis of human renal biopsy specimens revealed that PPAR-δ protein was detected in the HMC of glomeruli with moderately proliferative changes. In the HMC, both GW0742, an authentic PPAR-δ agonist, and telmisartan enhanced PPAR response element (PPRE)-luciferase activity dose dependently, and these increases were blunted by GSK0660, a specific PPAR-δ antagonist, but not by GW9662, a PPAR-γ antagonist. Telmisartan also upregulated the expression of PPAR-δ target genes related to fatty acid oxidation; that is, heart type-fatty acid-binding protein and uncoupling protein-2. These effects were inhibited by both PPAR-δ antagonism and PPAR-δ gene silencing. Transforming growth factor-β1 (TGF-β1) increased the expression of plasminogen activator inhibitor-1 (PAI-1), TGF-β1 and collagen IV. The PAI-1 expression was mediated, at least in part by the phosphorylation of extracellular signal-regulated kinases (ERKs). Telmisartan suppressed TGF-β1-stimulated PAI-1 and collagen IV expression and ERK phosphorylation, and these effects were weakened by PPAR-δ antagonism, whereas eprosartan, a non-PPAR activating ARB, did not affect TGF-β1-stimulated PAI-1 expression. These results indicate that in HMC telmisartan activates endogenous PPAR-δ and may prevent TGF-β1-induced fibrotic changes by reducing ERK phosphorylation in a PPAR-δ-dependent manner, and thus, might be useful for treating hypertensive patients with renal and metabolic disorders.
authors.affiliation: Division of Nephrology, Department of Medicine, Faculty of Medical Sciences, School of Medicine, University of Fukui, Fukui, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mikami
authors.affiliation: 1] Division of Nephrology, Department of Medicine, Faculty of Medical Sciences, School of Medicine, University of Fukui, Fukui, Japan [2] Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Nephrology, Department of Medicine, Faculty of Medical Sciences, School of Medicine, 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: Kunio
authors.initials: K
authors.lastname: Torii
authors.affiliation: Division of Nephrology, Department of Medicine, Faculty of Medical Sciences, School of Medicine, University of Fukui, Fukui, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kasuno
authors.affiliation: Division of Nephrology, Department of Medicine, Faculty of Medical Sciences, School of Medicine, University of Fukui, Fukui, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Obama Municipal Hospital, Obama, Fukui, Japan.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Nephrology, Department of Medicine, Faculty of Medical Sciences, School of Medicine, 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* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D010766:Phosphorylation; D000077333:Telmisartan; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; C493408:FABP3 protein, human; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047494:PPAR delta; D053773:Transforming Growth Factor beta1; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D048049:Extracellular Signal-Regulated MAP Kinases; D000077333:Telmisartan