APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis

Area of Science:

• Nephrology
• Molecular Biology
• Pathogenesis of Kidney Disease

Background:

• Idiopathic membranous nephropathy (IMN) is a major cause of nephrotic syndrome in adults.
• Phospholipase A2 receptor 1 (PLA2R1) plays a critical role in the pathogenesis of PLA2R1-related IMN.
• The precise molecular mechanisms underlying IMN pathogenesis and treatment remain incompletely understood.

Purpose of the Study:

• To investigate the expression changes of activated protein C (APC) and PLA2R1 in IMN patients.
• To elucidate the molecular mechanism by which APC influences podocyte apoptosis and PLA2R1 expression in IMN.
• To explore the potential of APC as a targeted therapy for IMN.

Main Methods:

• Quantification of APC and PLA2R1 expression using qPCR in IMN patients.
• Establishment of a zymosan-activated serum (ZAS)-induced IMN podocyte model in vitro.
• Assessment of podocyte apoptosis via flow cytometry and caspase-3 assay.
• Detection of protein expression levels (APC, p-ERK1/2, ERK1/2, YB-1, PLA2R1) using western blotting.
• Analysis of the YB-1 and PLA2R1 regulatory relationship using a dual fluorescent reporter system.

Main Results:

• IMN patients exhibited increased PLA2R1 expression and decreased APC expression.
• In vitro, APC addition to podocytes enhanced ERK1/2 phosphorylation.
• APC promoted YB-1 nuclear translocation, leading to reduced PLA2R1 expression at the transcriptional level.
• APC treatment inhibited podocyte apoptosis.

Conclusions:

• This study identifies APC as a novel therapeutic agent for IMN.
• APC ameliorates IMN by modulating podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 signaling axis.
• APC represents a promising targeted therapy for IMN patients with elevated PLA2R1 levels.