Downregulation of PPAR alpha mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells

Immunoglobulin A nephropathy (IgAN) is the commonest primary glomerulonephritis, and a major cause of end-stage renal disease; however, its pathogenesis requires elucidation. Here, a hub gene, FABP1, and signaling pathway, PPAR alpha, were selected as key in IgAN pathogenesis by combined weighted gene correlation network analysis of clinical traits and identification of differentially expressed genes from three datasets. FABP1 and PPAR alpha levels were lower in IgAN than control kidney, and linearly positively correlated with one another, while FABP1 levels were negatively correlated with urinary albumin-to-creatinine ratio, and GPX4 levels were significantly decreased in IgAN. In human mesangial cells (HMCs), PPAR alpha and FABP1 levels were significantly decreased after Gd-IgAl stimulation and mitochondria appeared structurally damaged, while reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly increased, and glutathione and GPX4 decreased, relative to controls. GPX4 levels were decreased, and those of ACSL4 increased on siPPAR alpha and siFABP1 siRNA treatment. In PPAR alpha lentivirus-transfected HMCs stimulated by Gd-IgAl, ROS, MDA, and ACSL4 were decreased; glutathione and GPX4, and immunofluorescence colocalization of PPAR alpha and GPX4, increased; and damaged mitochondria reduced. Hence, PPAR alpha pathway downregulation can reduce FABP1 expression, affecting GPX4 and ACSL4 levels, causing HMC ferroptosis, and contributing to IgAN pathogenesis.

Automated summary

IgA nephropathy (IgAN) is the most common primary glomerulonephritis and a major cause of end-stage renal disease. The downregulation of PPAR alpha pathway affects FABP1 and GPX4 levels, leading to ferroptosis in human mesangial cells (HMCs) and contributing to the pathogenesis of IgAN.