ADRB2 Overexpression Reverses Plasma Gelsolin-Induced TGF-β1 Upregulation in Mesangial Cells of IgA Nephropathy

Background: IgA nephropathy (IgAN), a common glomerulonephritis, is characterized by glomerular deposition of IgA-containing immune complexes, which drive mesangial cell proliferation and extracellular matrix synthesis through transforming growth factor beta 1 (TGF-β1) overexpression. Previous studies demonstrated abundant plasma gelsolin (pGSN) deposition in IgAN glomeruli, which promoted TGF-β1 expression. However, the molecular mechanisms by which pGSN modulates TGF-β1-mediated fibrosis in mesangial cells remain unclear. This study aimed to elucidate these mechanisms and identify potential therapeutic targets for inhibiting glomerular fibrosis in IgAN. Methods: Human glomerular mesangial cells (HMCs) were stimulated with pGSN. Transcriptome sequencing was applied to screen for key regulators of TGF-β1. Identified factors and TGF-β1 expression were validated by quantitative polymerase chain reaction (qPCR), western blot (WB), and immunofluorescence (IF). The functional role of the candidate regulator, adrenoceptor beta 2 (ADRB2), was further investigated using protein–protein interaction prediction and ADRB2 overexpression assays, including under co-stimulation with polymeric IgA1 (pIgA1). Results: Transcriptome sequencing revealed the cyclic adenosine monophosphate (cAMP) pathway gene ADRB2 as a potential fibrosis regulator. Stimulation of HMCs with pGSN reduced ADRB2 (p < 0.01) and cAMP dependent protein kinase (PKA) (p < 0.01) expression, while significantly increasing TGF-β1 (p < 0.001). Conversely, ADRB2 overexpression increased ADRB2 (p < 0.001) and PKA (p < 0.001) levels while decreasing TGF-β1 (p < 0.001). Notably, ADRB2 overexpression reversed the TGF-β1 upregulation induced by combined pGSN and pIgA1 stimulation. Conclusion: pGSN synergizes with pIgA1 to enhance TGF-β1 expression and glomerular fibrosis in IgAN by suppressing the ADRB2/cAMP signaling pathway. ADRB2 may represent a promising therapeutic target for antifibrotic strategies in IgAN.