We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis.
- Authors
Sugimoto, Hikaru; LeBleu, Valerie S; Bosukonda, Dattatreyamurty; Keck, Peter; Taduri, Gangadhar; Bechtel, Wibke; Okada, Hirokazu; Carlson, William, Jr; Bey, Philippe; Rusckowski, Mary; Tampe, Björn; Tampe, Desiree; Kanasaki, Keizo; Zeisberg, Michael; Kalluri, Raghu
- 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.
- Publication
Nature medicine, 2012, Vol 18, Issue 3, p396
- ISSN
1546-170X
- Publication type
Journal Article
- DOI
10.1038/nm.2629