title: Combination of cilostazol and probucol protected podocytes from lipopolysaccharide-induced injury by both anti-inflammatory and anti-oxidative mechanisms.
abstract: Podocytes are essential for maintaining kidney glomerular functions. Injuries to podocyte are closely related to the pathological process of proteinuria. However, a treatment for podocyte injury has still not been established. Cilostazol (CSZ) and probucol (PBC) have been shown to possess renoprotective effects. Therefore, we evaluated these drugs in a lipopolysaccharide (LPS)-induced podocyte injury model. 7-week-old female C57BL/6J mice were fed a normal diet or a diet containing 0.3% CSZ, 0.5% PBC, or both for 10 days. Then, mice were intraperitoneally injected with 13 μg g-1body weight LPS. Both CSZ and PBC decreased LPS-induced albuminuria and co-administration was found to be most effective. These treatments ameliorated the upregulation of monocyte chemoattractant protein 1. In cultured podocytes, CSZ suppressed LPS-induced activation of nuclear factor-kappa B (NF-κB) and phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). PBC reduced LPS-induced activation of NF-κB and reactive oxygen species production. Furthermore, PBC decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase4 expression. Our findings suggest that CSZ and PBC are able to inhibit podocyte-injury through different mechanisms, indicating that a combination of these two old drugs is a good treatment option to protect podocytes from injury.
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: He
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Eastern Chiba Medical Center, Togane, Chiba, 283-8686, Japan.
authors.forename: Harukiyo
authors.initials: H
authors.lastname: Kawamura
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. minoru.takemoto@faculty.chiba-u.jp.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. minoru.takemoto@faculty.chiba-u.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takemoto
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maezawa
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Ishibashi
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hattori
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Yamaga
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Ide
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Ide
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Yu-karigaoka Tokuyama Clinic, Sakura, Chiba, 285-0850, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Tokuyama
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.|Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D000077407:Cilostazol; D019610:Cytoprotection; D004195:Disease Models, Animal; D005260:Female; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000074663:NADPH Oxidase 4 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011341:Probucol / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013777:Tetrazoles; C482199:lipopolysaccharide, E coli O55-B5; D000074663:NADPH Oxidase 4; C422943:Nox4 protein, mouse; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077407:Cilostazol; D011341:Probucol
keywords: Inflammation; Lipopolysaccharide; Oxidative stress; Podocyte