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Protective effects of C-type natriuretic peptide on cisplatin-induced nephrotoxicity in Mice

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Abstract

Purpose

Cisplatin is a highly effective chemotherapeutic agent used to treat various malignancies, but its utility is compromised by its nephrotoxicity. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, exhibits anti-inflammatory effects by activating its specific receptor, guanylyl cyclase (GC)-B. CNP and GC-B receptor are known to be expressed in both the vascular endothelium and the kidney. The objective of this study was to investigate the renoprotective effects of CNP in a mouse model of cisplatin-induced nephrotoxicity.

Methods

C57BL/6 mice were divided into three groups: normal control mice; cisplatin (20 mg/kg, intraperitoneal) mice treated with vehicle; and cisplatin mice treated with CNP (2.5 µg/kg/min, subcutaneous). At 72 h after cisplatin injection, urine, blood and kidney samples were collected. Urine and blood samples were examined biochemically. Histological findings and gene expression in kidney tissue were evaluated.

Results

CNP reduced histological renal tubular damage and apoptosis induced by cisplatin and suppressed plasma blood urea nitrogen and creatinine levels, which were elevated by cisplatin administration. CNP treatment decreased the expression of kidney injury molecule-1 and monocyte chemoattractant protein-1, which were elevated in the kidney by cisplatin administration. CNP treatment attenuated the decrease in GC-B expression in cisplatin-induced kidney injury.

Conclusions

The present study is the first to show that CNP inhibits nephrotoxicity and kidney cell damage induced by cisplatin. The mechanism of action may involve down-regulation of inflammatory cytokine expression in cisplatin-induced kidney injury and attenuation of apoptosis in renal tubular cells.

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Young Scientists (JSPS KAKENHI Grant Number 26861135) and a Grant from the Takeda Science Foundation.

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan

    Toru Kimura, Takashi Nojiri, Shin Ishikane, Mikiya Miyazato & Kenji Kangawa

  2. Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan

    Toru Kimura, Takashi Nojiri, Yasushi Shintani, Masayoshi Inoue & Meinoshin Okumura

  3. Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan

    Hiroshi Hosoda

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  1. Toru Kimura
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  2. Takashi Nojiri
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Correspondence to Toru Kimura.

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Kimura, T., Nojiri, T., Hosoda, H. et al. Protective effects of C-type natriuretic peptide on cisplatin-induced nephrotoxicity in Mice. Cancer Chemother Pharmacol 75, 1057–1063 (2015). https://doi.org/10.1007/s00280-015-2734-7

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  • DOI: https://doi.org/10.1007/s00280-015-2734-7

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