Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis
Department of Radiology, Division of Nuclear Medicine
Angiotensin-Converting Enzyme Inhibitors; Animals; 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
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.
DOI of Published Version
Nat Med. 2012 Feb 5;18(3):396-404. doi: 10.1038/nm.2629. Link to article on publisher's site
Sugimoto, Hikaru; LeBleu, 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; and Kalluri, Raghu, "Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis" (2012). Radiology Publications and Presentations. 109.