Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis
LeBleu, Valerie S
Carlson, William Jr.
UMass Chan AffiliationsDepartment of Radiology, Division of Nuclear Medicine
KeywordsAngiotensin-Converting Enzyme Inhibitors
Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein Receptors, Type I
Bone Morphogenetic Protein Receptors, Type II
Bone Morphogenetic Proteins
Transforming Growth Factor beta
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AbstractMolecules 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.
SourceNat Med. 2012 Feb 5;18(3):396-404. doi: 10.1038/nm.2629. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/48000
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