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

• Published in: Nature medicine Vol. 18; no. 3; pp. 396 - 404
• Main Authors: Sugimoto, Hikaru, LeBleu, Valerie S, Bosukonda, Dattatreyamurty, Keck, Peter, Taduri, Gangadhar, Bechtel, Wibke, Okada, Hirokazu, Carlson, Jr, William, Bey, Philippe, Rusckowski, Mary, Tampe, Björn, Tampe, Desiree, Kanasaki, Keizo, Zeisberg, Michael, Kalluri, Raghu
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2012
• Subjects: Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Apoptosis - genetics; Bone Morphogenetic Protein Receptors - genetics; Bone Morphogenetic Protein Receptors - metabolism; Bone Morphogenetic Protein Receptors, Type I - genetics; Bone Morphogenetic Protein Receptors, Type I - metabolism; Bone Morphogenetic Protein Receptors, Type II - genetics; Bone Morphogenetic Protein Receptors, Type II - metabolism; Bone Morphogenetic Proteins - agonists; Bone Morphogenetic Proteins - metabolism; Captopril - pharmacology; Cellular signal transduction; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Enzyme inhibitors; Epithelial-Mesenchymal Transition; Fibrosis - metabolism; Gene expression; Inflammation - genetics; Inflammation - metabolism; Kidney - injuries; Kidney - metabolism; Kidney diseases; Kidney Tubules - metabolism; Kidneys; Kinases; Mice; Peptide Library; Peptides - chemical synthesis; Peptides - metabolism; Peptides - pharmacokinetics; Pharmacology; Physiological aspects; Protein kinases; Rats; Rats, Sprague-Dawley; Regeneration - genetics; Risk factors; Rodents; Signal Transduction; Smad3 Protein - genetics; Smad3 Protein - metabolism; Structure-Activity Relationship; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2629

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.