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Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease

Nature Medicine volume 11, pages 387–393 (2005)Cite this article

Abstract

The bone morphogenetic proteins (BMPs) profoundly affect embryonic development, differentiation and disease. BMP signaling is suppressed by cysteine-rich domain proteins, such as chordin, that sequester ligands from the BMP receptor. We describe a novel protein, KCP, with 18 cysteine-rich domains. Unlike chordin, KCP enhances BMP signaling in a paracrine manner. Smad1-dependent transcription and phosphorylated Smad1 (P-Smad1) levels are increased, as KCP binds to BMP7 and enhances binding to the type I receptor. In vivo, Kcp−/− mice are viable and fertile. Because BMPs have a pivotal role in renal disease, we examined the phenotype of Kcp−/− mice in two different models of renal injury. Kcp−/− animals show reduced levels of P-Smad1, are more susceptible to developing renal interstitial fibrosis, are more sensitive to tubular injury and show substantial pathology after recovery. The data indicate an important role for KCP in attenuating the pathology of renal fibrotic disease.

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Figure 1: The mouse KCP is a secreted cysteine-rich domain protein.
Figure 2: The developmental expression pattern of Kcp.
Figure 3: KCP enhances BMP-mediated gene expression.
Figure 4: Generation and analysis of Kcp−/− mutants.
Figure 5: Analysis of obstructed and contralateral kidneys.
Figure 6: Recovery from acute tubular injury.

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Acknowledgements

We thank P. ten Dijke for the BRE-Luc reporter, E. Neilson for the anti-FSP1 antibody, A. Eddy for advice with the UUO model, and R. Wiggins, E. Fearon and K. Cadigan for reading and discussions. Gene targeting was done in the University of Michigan Transgenic Animal Model Core with the assistance of E. Hughes and T. Saunders. This work is supported by US National Institutes of Health grants DK062914 and PKD Grant-in-Aid to G.R.D., DK02803 to S.R.P., and HL52285 to S.H.P.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan, 1301 Catherine Street, Ann Arbor, 48109, Michigan, USA

    Jingmei Lin, Eun Ah Cho, Inna Levitan, Matthew Ullenbruch, Sem H Phan & Gregory R Dressler

  2. Department of Internal Medicine, University of Michigan, 3110 Taubman, Ann Arbor, 48109, Michigan, USA

    Sanjeevkumar R Patel

  3. Department of Urology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Xu Cheng & John M Park

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  1. Jingmei Lin
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Correspondence to Gregory R Dressler.

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Lin, J., Patel, S., Cheng, X. et al. Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease. Nat Med 11, 387–393 (2005). https://doi.org/10.1038/nm1217

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