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

Abstract

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, PPARα, 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 PPARα 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), PPARα and FABP1 levels were significantly decreased after Gd-IgA1 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 siPPARα and siFABP1 siRNA treatment. In PPARα lentivirus-transfected HMCs stimulated by Gd-IgA1, ROS, MDA, and ACSL4 were decreased; glutathione and GPX4, and immunofluorescence colocalization of PPARα and GPX4, increased; and damaged mitochondria reduced. Hence, PPARα pathway downregulation can reduce FABP1 expression, affecting GPX4 and ACSL4 levels, causing HMC ferroptosis, and contributing to IgAN pathogenesis.

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

“…Previous studies have demonstrated that CYP11B2 [763], FLI1 [764], SLC7A7 [765], NPNT (nephronectin) [766], AZGP1 [767], TREH (trehalase) [768], CCR1 [769], CNTN1 [770], VCAM1 [771] and GBP3 [772] are linked with the development mechanisms of glomerulonephritis. A recent study revealed that FABP1 [773] and NPHS1 [774] expression was altered in IgA nephropathy. CLCN5 [775], ENPEP (glutamylaminopeptidase) [776], CCR1 [777] and NPHS1 [778] have been identified in focal segmental glomerulosclerosis.…”

Molecular insight in intrarenal inflammation affecting four main types of cells in nephrons in IgA nephropathy

“…Dai et al ( 49 ) demonstrated that histone deacetylase is upregulated in mesangial cells from patients with IgAN and subsequently activates TGF-β/recombinant mothers against decapentaplegic homolog 2/3 (Smad2/3) and Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) signaling pathways for cellular proliferation and ECM expansion. Gd-IgA1 could also induce mesangial cell ferroptosis by damaging mitochondria and increasing reactive oxygen species and malondialdehyde ( 50 ).…”

Novel Insight into Ferroptosis in Kidney Diseases

“…Some studies revealed that PPARα pathway downregulation reduced FABP1 expression, which led to IgA nephropathy by increasing iron prolapse in human mesangial cells [56]. Other studies indicated that the hub gene, FABP1 and the PPAR signaling pathway were ruled out as being closely related to IgAN [56]. In terms of its mechanism, FABP1 controls GPX4 and ACSL4 through PPAR, which causes IgAN and leads to ferroptosis in the in vitro HMC model of IgAN [56].Therefore, interfering with PPAR signaling to prevent ferroptosis is a possibility for halting or slowing the progression of IgAN [56].…”

“…Recent evidence has indicated that ferroptosis is an area of progress related to immunoglobulin A nephropathy (IgAN), the most common type of primary glomerulonephritis and a major cause of end-stage renal disease [55]. Some studies revealed that PPARα pathway downregulation reduced FABP1 expression, which led to IgA nephropathy by increasing iron prolapse in human mesangial cells [56]. Other studies indicated that the hub gene, FABP1 and the PPAR signaling pathway were ruled out as being closely related to IgAN [56].…”

“…Some studies revealed that PPARα pathway downregulation reduced FABP1 expression, which led to IgA nephropathy by increasing iron prolapse in human mesangial cells [56]. Other studies indicated that the hub gene, FABP1 and the PPAR signaling pathway were ruled out as being closely related to IgAN [56]. In terms of its mechanism, FABP1 controls GPX4 and ACSL4 through PPAR, which causes IgAN and leads to ferroptosis in the in vitro HMC model of IgAN [56].…”