Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis.
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.
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Hikaru
H
Sugimoto
Valerie S
VS
LeBleu
Dattatreyamurty
D
Bosukonda
Peter
P
Keck
Gangadhar
G
Taduri
Wibke
W
Bechtel
Hirokazu
H
Okada
William
W
Carlson
Philippe
P
Bey
Mary
M
Rusckowski
Björn
B
Tampe
Desiree
D
Tampe
Keizo
K
Kanasaki
Michael
M
Zeisberg
Raghu
R
Kalluri
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000819:agonists* / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000293:injuries* / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000235:genetics*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D019485:Bone Morphogenetic Proteins; D019151:Peptide Library; D010455:Peptides; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D002216:Captopril; C498219:Bmpr2 protein, mouse; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II