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Long-term treatment with EGFR inhibitor erlotinib attenuates renal inflammatory cytokines but not nephropathy in Alport syndrome mouse model

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Abstract

Background

Alport syndrome (AS) is a hereditary kidney disease caused by mutation of type IV collagen. Loss of collagen network induces collapse of glomerular basement membrane (GBM) structure. The previous studies showed that upregulation of some tyrosine kinase receptors signaling accompanied GBM disorder in AS mouse model. EGFR signaling is one of the well-known receptor kinase signaling that is involved in glomerular diseases. However, whether EGFR signaling is relevant to AS progression is still uninvestigated. Here, we determined the involvement of EGFR in AS and the effect of suppressing EGFR signaling by erlotinib treatment on AS progression.

Methods

Phosphorylated EGFR expression was investigated by Western blotting analysis and immunostaining of kidney tissues of Col4a5 mutant mice (a mouse model of X-linked AS). To check the effect of blocking EGFR signaling in AS, we administered erlotinib to AS mice once a day (10 mg/kg/day) orally for 18 weeks. Renal function parameters (proteinuria, serum creatinine, and BUN) and renal histology were assessed, and the gene expressions of inflammatory cytokines were analyzed in renal tissues.

Results

Phosphorylated EGFR expression was upregulated in AS mice kidney tissues. Erlotinib slightly reduced the urinary protein and suppressed the expression of renal injury markers (Lcn2, Lysozyme) and inflammatory cytokines (Il-6, Il-1β and KC). Erlotinib did not improve renal pathology, such as glomerular sclerosis and fibrosis.

Conclusion

These findings suggest that EGFR signaling is upregulated in kidney, but although inhibiting this signaling pathway suppressed renal inflammatory cytokines, it did not ameliorate renal dysfunction in AS mouse model.

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Acknowledgements

This work was supported by the Grants-in-Aid for Science Research from the Ministry of Education, Science, Sports, and Culture of Japan (MEXT) (#22390015 to H.K. and #23590082 to M.S.), and by the Program for Leading Graduate Schools HIGO (Health life science: Interdisciplinary and Glocal Oriented), MEXT, Japan.

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Authors and Affiliations

  1. Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Japan

    Kohei Omachi, Rui Miyakita, Ryosuke Fukuda, Yukari Kai, Mary Ann Suico, Tsubasa Yokota, Misato Kamura, Tsuyoshi Shuto & Hirofumi Kai

  2. Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto City, Kumamoto, Japan

    Kohei Omachi & Misato Kamura

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  1. Kohei Omachi
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  2. Rui Miyakita
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  3. Ryosuke Fukuda
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  4. Yukari Kai
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  9. Hirofumi Kai
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Correspondence to Hirofumi Kai.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care and Use committee of Kumamoto University (#25-230E). This article does not contain any studies with human participants performed by any of the authors.

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Omachi, K., Miyakita, R., Fukuda, R. et al. Long-term treatment with EGFR inhibitor erlotinib attenuates renal inflammatory cytokines but not nephropathy in Alport syndrome mouse model. Clin Exp Nephrol 21, 952–960 (2017). https://doi.org/10.1007/s10157-017-1386-9

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  • DOI: https://doi.org/10.1007/s10157-017-1386-9

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