Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis
Authors
Sugimoto, HikaruLeBleu, Valerie S
Bosukonda, Dattatreyamurty
Keck, Peter
Taduri, Gangadhar
Bechtel, Wibke
Okada, Hirokazu
Carlson, William Jr.
Bey, Philippe
Rusckowski, Mary
Tampe, Bjorn
Tampe, Desiree
Kanasaki, Keizo
Zeisberg, Michael
Kalluri, Raghu
UMass Chan Affiliations
Department of Radiology, Division of Nuclear MedicineDocument Type
Journal ArticlePublication Date
2012-02-05Keywords
Angiotensin-Converting Enzyme InhibitorsAnimals
Apoptosis
Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein Receptors, Type I
Bone Morphogenetic Protein Receptors, Type II
Bone Morphogenetic Proteins
Captopril
Diabetic Nephropathies
Epithelial-Mesenchymal Transition
Fibrosis
Inflammation
Kidney
Kidney Tubules
Mice
Peptide Library
Peptides
Rats
Rats, Sprague-Dawley
Regeneration
Signal Transduction
Smad3 Protein
Structure-Activity Relationship
Transforming Growth Factor beta
Biochemistry
Cell Biology
Radiology
Therapeutics
Metadata
Show full item recordAbstract
Molecules associated with the transforming growth factor beta (TGF-beta) superfamily, such as bone morphogenic proteins (BMPs) and TGF-beta, 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-beta1-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.Source
Nat Med. 2012 Feb 5;18(3):396-404. doi: 10.1038/nm.2629. Link to article on publisher's siteDOI
10.1038/nm.2629Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48000PubMed ID
22306733Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/nm.2629
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