Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis
| Autor: | Gangadhar Taduri, Peter Keck, Raghu Kalluri, Philippe Bey, Hikaru Sugimoto, Désirée Tampe, Mary Rusckowski, Keizo Kanasaki, Dattatreyamurty Bosukonda, Valerie S. LeBleu, Michael Zeisberg, Wibke Bechtel, Hirokazu Okada, William D. Carlson, Björn Tampe |
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| Rok vydání: | 2012 |
| Předmět: |
0303 health sciences
medicine.medical_specialty biology Regeneration (biology) Kidney metabolism General Medicine Transforming growth factor beta Bone morphogenetic protein medicine.disease General Biochemistry Genetics and Molecular Biology 3. Good health BMPR2 03 medical and health sciences 0302 clinical medicine Endocrinology Fibrosis 030220 oncology & carcinogenesis Internal medicine Renal fibrosis biology.protein Cancer research medicine Signal transduction 030304 developmental biology |
| Zdroj: | Nature Medicine. 18:396-404 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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