Downregulation of CD36 alleviates IgA nephropathy by promoting autophagy and inhibiting extracellular matrix accumulation in mesangial cells

Abstract

Background: Immunoglobulin A Nephropathy (IgAN) is a leading cause of end-stage renal disease (ESRD), but its pathogenesis remains unclear, and specific therapies are currently lacking. Consequently, identifying novel differentially expressed genes (DEGs) and therapeutic targets is of paramount importance to IgAN.

Methods: The Gene Expression Omnibus (GEO) databases GSE37460 and GSE104948, containing data from renal tissue of patients with IgAN and normal controls, were screened for DEGs, followed by enrichment pathway analysis. The potential key gene for IgAN, CD36, was identified through the single-cell sequencing dataset GSE166793 and histopathological analysis of patients with IgAN. Clinical and pathological data from patients with IgAN were collected to analyze the correlation between CD36 expression and various indicators in renal tissue, thereby evaluating the influence of CD36 on IgAN progression. The accuracy of the risk score model was assessed using receiver operating characteristic (ROC) curve analysis. Finally, CD36 expression was knocked down to explore its regulatory role in polymeric IgA1 (pIgA1)-stimulated mouse mesangial cells (MCs).

Results: CD36 was identified as a key DEG from two GEO databases and a single-cell sequencing dataset. Compared to peritumoral normal tissues, CD36 expression levels were significantly increased in the IgAN group. Statistically significant differences were observed between M0 and M1, E0 and E1, S0 and S1, C0 and C1-2 in the updated Oxford Classification. CD36 expression showed positive correlations with 24-hour proteinuria, serum creatinine, and levels of fibrosis-related and autophagy-related factors in renal tissue. Additionally, CD36 and fibrosis-related factors were significantly elevated in MCs following pIgA1 stimulation. CD36 knockdown resulted in decreased extracellular matrix (ECM) accumulation in pIgA1-stimulated MCs. RNA-seq analysis of MCs with CD36 knockdown revealed significant alterations in autophagy and CD36 silencing restored autophagy levels in MCs treated with the autophagy inhibitor 3MA.

Conclusion: Our study confirmed that CD36 expression increases with the clinical progression of IgAN and CD36 knockdown alleviates MCs injury by inhibiting ECM accumulation and restoring autophagy.

Keywords: Autophagy; CD36; Fibrosis; IgA nephropathy; Mesangial cells.