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

Abstract

Molecules associated with TGF-β superfamily such as BMPs and TGF-β are key regulators of inflammation, apoptosis and cellular transitions. Here, we demonstrate that the BMP receptor activin–like kinase 3 (Alk3) is elevated early in response to kidney injury and its deletion in the tubular epithelium leads to enhanced TGF-β1 / Smad3 signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3 mediated signaling. Structure–function analysis of Alk3 / BMP / BMPRII ligand–receptor complex coupled with synthetic organic chemistry led us to construct a library of small peptide agonists of BMP signaling that function via Alk3 receptor. One such peptide agonist, THR–123, suppressed inflammation, apoptosis epithelial–to–mesenchymal transition program, and reversed fibrosis in mouse models of acute and chronic injury. Combining THR–123 and angiotensin–converting enzyme inhibitor, captopril, exhibited additive therapeutic benefit in controlling fibrosis. Our studies demonstrate that BMP signaling agonists constitute a new line of therapeutic agents with a potential utility in the clinic to induce regeneration, repair and reverse fibrosis.