PP2A Catalytic Subunit α promotes fibroblast activation and kidney fibrosis via ERK pathway

Abstract Protein Phosphatase 2A (PP2A), a main serine/threonine phosphatase, plays a profibrotic role in the development of different organs. However, the role and mechanisms of PP2Acα in fibroblast activation and kidney fibrosis are not fully known. Here we found that PP2Acα expression was upregulated in kidney tissue of chronic kidney disease (CKD) patients and unilateral ureter obstructive (UUO) mice. Ablation of fibroblast PP2Acα alleviates fibroblast activation and kidney fibrosis in mouse kidneys with UUO nephropathy compared with the control littermates. In primary cultured fibroblasts, PP2Acα deletion restrains TGFβ1-induced fibroblast activation, which is accompanied by increased phosphorylation of the extracellular regulated kinase (ERK). Blocking ERK pathway activation by PD98059 could promote fibroblast activation, indicating that PP2Acα promotes TGFβ1-induced fibroblast activation via suppressing ERK pathway. Consistently, in vivo, the activation of ERK pathway was upregulated by PP2Acα ablation in kidney fibroblasts. Together, these data uncover that PP2Acα may promote fibroblast activation and kidney fibrosis via suppressing ERK pathway, suggesting that targeting PP2Acα may provide a therapeutic effect for CKD.