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

Area of Science:

• Biochemistry
• Cell Biology
• Nephrology

Background:

• Protein Phosphatase 2A (PP2A) is a key serine/threonine phosphatase implicated in organ fibrosis.
• The specific role and mechanisms of PP2A catalytic subunit alpha (PP2Acα) in kidney fibrosis and fibroblast activation remain unclear.

Purpose of the Study:

• To investigate the role of PP2Acα in fibroblast activation and kidney fibrosis.
• To elucidate the underlying molecular mechanisms involving the extracellular regulated kinase (ERK) pathway.

Main Methods:

• Analysis of PP2Acα expression in human chronic kidney disease (CKD) tissues and mouse models of kidney fibrosis (unilateral ureter obstruction - UUO).
• Fibroblast-specific PP2Acα ablation in UUO mice.
• In vitro studies using primary cultured fibroblasts treated with TGFβ1.
• Pharmacological inhibition of the ERK pathway using PD98059.

Main Results:

• PP2Acα expression was elevated in CKD patient kidneys and UUO mouse kidneys.
• Ablation of fibroblast PP2Acα attenuated kidney fibrosis and fibroblast activation in UUO mice.
• PP2Acα deletion inhibited TGFβ1-induced fibroblast activation by increasing ERK phosphorylation.
• Inhibition of the ERK pathway exacerbated fibroblast activation, confirming PP2Acα's suppressive role.

Conclusions:

• PP2Acα promotes fibroblast activation and kidney fibrosis by suppressing the ERK pathway.
• Targeting PP2Acα represents a potential therapeutic avenue for managing CKD and related fibrotic conditions.