Activin-like kinase 3 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.

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

“…However, our data suggests that this is unlikely to occur via a direct interaction between Grem1 and BMP-7, given their low binding affinity. Small molecules such as tilerone (which induces BMP-7) and Thr123 (which activates the Alk3 BMP receptor) have been shown to reduce kidney fibrosis in vivo [47,48]. Together with a recent report showing that an anti-Grem1 antibody can reduce fibrosis in a model of pulmonary artery hypertension (PAH) [49], these data illustrate that manipulation of the Grem1-BMP signalling axis may still be a useful therapeutic avenue for the treatment of diabetic kidney disease.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Other antifibrotic interventions in the system are focused on modulators of TGF-bioactivity, such as BMP-7 or BMP antagonists such as USAG-1 (253,261,262). BMP7 receptor Alk3 (263), and its downstream mediator Trps1 (264), have also been shown to be involved in kidney fibrosis. Other members of the BMP family also play a role, BMP6 being anti-fibrotic (265) and BMP1-3 being profibrotic (266).…”

Immune-mediated inflammatory diseases: progress in molecular pathogenesis and therapeutic strategies

“…Alk3 is the predominant receptor through which BMP-7 exerts its functions. Alk3 is elevated early in diseased kidneys after injury and is important for kidney regeneration and reversal of fibrosis [14]. Kalluri reported development of The European Workshop on Immune-Mediated Inflammatory Diseases aims to exchange scientific knowledge and promote the collaboration between various disciplines (rheumatology, dermatology and gastroenterology) among physicians and scientists.…”