Aims: Interventions to inhibit oxidative stress and apoptosis, important pathogenic contributors toward the progression of chronic kidney disease (CKD), are not well established. Here, we investigated the role of a transforming growth factor beta (TGFβ) superfamily neutralizing protein, follistatin (FST), in the regulation of apoptosis and oxidative stress in glomerular mesangial cells (MCs) and in the progression of CKD. Results: The endoplasmic reticulum (ER) stress inducer thapsigargin (Tg), known to cause MC apoptosis, led to a post-translational increase in the expression of FST. Recombinant FST protected, whereas FST downregulation augmented, Tg-induced apoptosis without affecting Ca2+ release or ER stress induction. Although activins are the primary ligands neutralized by FST, their inhibition with neutralizing antibodies did not affect Tg-induced apoptosis. Instead, FST protected against Tg-induced apoptosis through neutralization of reactive oxygen species (ROS) independently of its ability to neutralize activins. Importantly, administration of FST to mice with CKD protected against renal cell apoptosis and oxidative stress. This was associated with improved kidney function, reduced albuminuria, and attenuation of fibrosis. Innovation and Conclusion: Independent of its activin neutralizing ability, FST protected against Tg-induced apoptosis through neutralization of ROS and consequent suppression of oxidative stress, seen both in vitro and in vivo. Importantly, FST also ameliorated fibrosis and improved kidney function in CKD. FST is, thus, a novel potential therapeutic agent for delaying the progression of CKD. Antioxid. Redox Signal. 31, 551-571.
Keywords: apoptosis; chronic kidney disease; mesangial cells; oxidative stress.