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Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome

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Abstract

Childhood nephrotic syndrome is mainly caused by minimal change disease which is named because only subtle ultrastructural alteration could be observed at electron microscopic level in the pathological kidney. Glomerular podocytes are presumed to be the target cells whose protein sieving capability is compromised by a yet unidentified permeability perturbing factor. In a cohort of children with non-hereditary idiopathic nephrotic syndrome, we found the complement fragment C5a was elevated in their sera during active disease. Administration of recombinant C5a induced profound proteinuria and minimal change nephrotic syndrome in mice. Purified glomerular endothelial cells, instead of podocytes, were demonstrated to be responsible for the proteinuric effect elicited by C5a. Further studies depicted a signaling pathway involving Rho/Rho-associated kinase/myosin activation leading to endothelial cell contraction and cell adhesion complex breakdown. Significantly, application of Rho-associated kinase inhibitor, Y27632, prevented the protein leaking effects observed in both C5a-treated purified endothelial cells and mice. Taken together, our study identifies a previously unknown mechanism underlying nephrotic syndrome and provides a new insight toward identifying Rho-associated kinase inhibition as an alternative therapeutic option for nephrotic syndrome.

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Acknowledgments

This study is supported by National Science Council (NSC100-2325-B-002-029) and National Taiwan University Hospital grants (aNTUH99P21-1 and 98P26-1) to T.S. Jou, National Science Council grants (NSC100-2314-B-002-105, NSC101-2314-B-002-062, and NSC102-2314-B-002-064) to Y.K. Tsau, and National Taiwan University Hospital grants (NTUH100 M-1741, 101 M-1997 and 102 M-2316) to I.J. Tsai. We thank the staff of the imaging core at the First Core Labs, National Taiwan University College of Medicine, for technical assistance.

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All the authors declared no competing interests.

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Authors and Affiliations

  1. Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    I-Jung Tsai, Yao-Hsu Yang & Yong-Kwei Tsau

  2. Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Chia-Hung Chou & Wan-Ting Liau

  3. Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Wei-Chou Lin

  4. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Yen-Hung Lin & Tzuu-Shuh Jou

  5. Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan

    Lu-Ping Chow

  6. Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan

    Hsiao-Hui Lee

  7. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Pei-Gang Kao & Tzuu-Shuh Jou

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  1. I-Jung Tsai
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Tsai, IJ., Chou, CH., Yang, YH. et al. Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome. Cell. Mol. Life Sci. 72, 3157–3171 (2015). https://doi.org/10.1007/s00018-015-1888-0

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