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Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis

Nature Medicine volume 18, pages 396–404 (2012)Cite this article

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Abstract

Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1–Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3–BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a _targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.

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Figure 1: Alk3 and BMP7 expression inversely correlate in kidneys developing progressive injury and fibrosis.
Figure 2: Synthesis and pharmacokinetics of THR-123.
Figure 3: THR-123 reverses renal fibrosis in mice with NTN.
Figure 4: THR-123 reverses the fibrosis associated with diabetic nephropathy.
Figure 5: Treatment with a combination of CPR and THR-123 inhibits the progression of fibrosis associated with advanced diabetic nephropathy.
Figure 6: Alk3 is a functional receptor for the activity of THR-123.

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Acknowledgements

This study was supported by US National Institutes of Health grants DK55001, DK061688, DK081576, DK074558, CA155370 CA163191, CA125550, CA151925 and the Else Kröner–Memorial–Stipend P58/05//EKMS 05/59 (M.Z.). V.S.L. is funded from the Research Training Grant in Gastroenterology (2T32DK007760–11). H.S. is funded by the Research Training Grant in Cardiovascular Biology (5T32HL007374–30). Mice with the Alk3flox/flox allele (Alk3f/f) were kindly provided by Y. Mishina, US National Institutes of Health under a material transfer agreement. γGT-Cre mice, NP-1 cells and the polyclonal antibody to FSP1 were provided by E. Neilson, Vanderbilt University Medical Center. We thank S. McGoohan for his technical assistance.

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Authors and Affiliations

  1. Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

    Hikaru Sugimoto, Valerie S LeBleu, Gangadhar Taduri, Wibke Bechtel, Hirokazu Okada, Keizo Kanasaki, Michael Zeisberg & Raghu Kalluri

  2. Thrasos Innovation Inc., Montreal, Quebec, Canada

    Dattatreyamurty Bosukonda, Peter Keck & William Carlson

  3. Division of Cardiology, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA

    William Carlson & Philippe Bey

  4. Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical College, Worcester, Massachusetts, USA

    Mary Rusckowski

  5. Department of Nephrology and Rheumatology, Goettingen University Medical Center, Georg August University, Goettingen, Germany

    Björn Tampe, Desiree Tampe, Michael Zeisberg & Raghu Kalluri

  6. Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA

    Raghu Kalluri

  7. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Raghu Kalluri

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  1. Hikaru Sugimoto
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Contributions

R.K. conceptually designed the strategy for this study, participated in discussions, provided intellectual input, supervised the studies and wrote the manuscript. H.S. performed experiments and analyzed the data. M.Z. participated in the discussions and performed experiments. W.B., P.K., D.B., W.C., M.R., P.B., G.T., H.O., D.T., B.T. and V.S.L. performed experiments, analyzed the data and edited the manuscript and generated the figures. K.K. and V.S.L. supervised in vitro experiments, helped in the writing of the manuscript and generated the figures.

Corresponding author

Correspondence to Raghu Kalluri.

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Competing interests

P.K., D.B., R.K., W.C. and P.B. hold equity in Thrasos, Inc.

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Sugimoto, H., LeBleu, V., Bosukonda, D. et al. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat Med 18, 396–404 (2012). https://doi.org/10.1038/nm.2629

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