Activin B mediates fibrosis in diabetic kidney disease

Abstract Diabetic kidney disease (DKD) is the leading cause of end stage kidney disease, driven in large part by progressive fibrosis. Activin A, a member of the transforming growth factor beta superfamily, has been implicated in the pathogenesis of DKD. Here, we demonstrate that activin B is significantly increased in human and murine models of DKD in both glomerular and tubulointerstitial compartments. High glucose induces time dependent increases in activin A and B secretion in mesangial cells and kidney fibroblasts, leading to enhanced extracellular matrix production. Mechanistically, both activins activate the canonical Smad3 pathway and promote a synthetic phenotype in mesangial cells via noncanonical MRTF-A and SRF signaling. Activin B secretion occurs later (72h) than that of activin A (48h), suggesting importance to chronic fibrotic remodeling. Inhibition of activin signaling via neutralizing antibodies, siRNA, or follistatin attenuates high glucose-induced fibrotic responses in both mesangial cells and fibroblasts. These findings reveal a synergistic and temporally distinct role for activins A and B in kidney cellular profibrotic responses and support their combined inhibition as a promising therapeutic strategy to mitigate fibrosis and preserve kidney function.