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Combination of cilostazol and probucol protected podocytes from lipopolysaccharide-induced injury by both anti-inflammatory and anti-oxidative mechanisms

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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−1 body 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.

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Acknowledgements

We wish to thank Mrs. Aki Watanabe and Mrs. Naoko Koizumi (Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine) for their valuable technical assistance.

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Authors and Affiliations

  1. Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Peng He, Harukiyo Kawamura, Minoru Takemoto, Yoshiro Maezawa, Takahiro Ishikawa, Ryoichi Ishibashi, Kenichi Sakamoto, Mayumi Shoji, Akiko Hattori, Masaya Yamaga, Shintaro Ide, Kana Ide, Aiko Hayashi, Kazuki Kobayashi & Koutaro Yokote

  2. Eastern Chiba Medical Center, Togane, Chiba, 283-8686, Japan

    Harukiyo Kawamura

  3. Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Minoru Takemoto, Yoshiro Maezawa, Takahiro Ishikawa, Ryoichi Ishibashi, Kenichi Sakamoto, Mayumi Shoji, Akiko Hattori, Masaya Yamaga, Shintaro Ide, Kana Ide, Aiko Hayashi, Kazuki Kobayashi & Koutaro Yokote

  4. Yu-karigaoka Tokuyama Clinic, Sakura, Chiba, 285-0850, Japan

    Hirotake Tokuyama

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  1. Peng He
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Correspondence to Minoru Takemoto.

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This study was carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH publication no. 85-23, revised 1985). The protocol was approved by the Committee on the Ethics of the Animal Care and Use of Chiba University, Japan (Permit Number: 25-255).

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He, P., Kawamura, H., Takemoto, M. et al. Combination of cilostazol and probucol protected podocytes from lipopolysaccharide-induced injury by both anti-inflammatory and anti-oxidative mechanisms. J Nephrol 30, 531–541 (2017). https://doi.org/10.1007/s40620-016-0361-y

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