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E-Poster Submission Deadline
Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
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IgA nephropathy (IgAN) is the most prevalent form of primary glomerulonephritis worldwide, accounting for over 50% of primary glomerular diseases in China and being a major contributor to end-stage renal disease. Mesangial cell proliferation and matrix deposition are the primary pathological features of IgAN.Macrophage polarization plays a pivotal role in the progression of IgAN disease. But its mechanism of action is not fully understood.
To explore the mechanisms of Astragaloside IV (AS-IV) in IgAN, we established an IgAN mouse model and mesangial cell injury model, and treated them with AS-IV. We found that AS-IV excellently reduced mesangial cell proliferation and matrix deposition while decreasing macrophage infiltration, and then delayed the injury of the kidney.
In the BSA/CCL4/LPS-induced IgAN mouse models, we observed elevated serum creatinine and 24-hour urinary protein levels, along with glomerular deposition of IgA, IgG, and C3 in IgAN mice. AS-IV significantly reduced urinary protein, serum creatinine, serum gd-IgA1, and decreased glomerular IgA, IgG, and C3 deposition(Fig.1). We observed significantly elevated α-smooth muscle actin (α-SMA) expression and substantial fibronectin (FN) deposition in the model group. In the mesangial cell injury model induced by gd-IgA1 stimulation, the expression of α-SMA and Ki67 was also increased. Treatment with AS-IV at different concentrations effectively inhibited mesangial cell proliferation and reduced matrix deposition(Fig.2). Additionally, no significant differences were observed between the valsartan group and the AS-IV group. Our analysis of serum inflammatory factors showed elevated CCL2 levels, with flow cytometry of renal cells showing substantial macrophage recruitment and M2 polarization (Fig.3). Furthermore, RNA sequencing results indicated remarkable CCL2 enrichment in the IgAN mice model group, suggesting multiple IgAN progression pathways associated with inflammatory signaling were activated(Fig.4). Clinical IgAN patient renal biopsy sections demonstrated ADAM19 expression predominantly in the mesangial region, while lower expression was observed in diabetic nephropathy (DN) or membranous nephropathy (MN)(Fig.5). In vivo and in vitro studies on mechanisms, we observed significant upregulation of ADAM19 and Notch1 in the model group, along with the notable upregulation of G1 / S-specific cyclin D1(Cyclin D) and proto-oncogene c-Myc(Myc), key downstream effectors of Notch(Fig.6). When ADAM19 expression was inhibited, Notch1 and its downstream factors were suppressed. And AS-IV demonstrated excellent inhibitory effects comparable to the ADAM19 inhibitor (SOR)(Fig.7). Overexpression of ADAM19 significantly enhanced glomerular mesangial cell proliferation and increased matrix deposition, along with elevated expression of Notch1 and its downstream factors. Dual-luciferase assays revealed that ADAM19 overexpression significantly enhanced binding to the promoters of CCL2, Cyclin D, and Myc, while markedly promoting macrophage recruitment(Fig.8).
Fig.1. AS-IV improved renal dysfunction and pathological injury in IgAN mice.
Fig.2. AS-IV alleviated mesangial cell proliferation and matrix deposition in vivo and in vitro.
Fig.3. AS-IV inhibits the release of inflammatory factors and regulates the infiltration of macrophages.
Fig.4. AS-IV reduces CCL2 accumulation and inhibits inflammatory pathway activation.
Fig.5. Adam19 expression in the mesangial area in IgAN patients was increased and regulates the activation of mesangial cells.
Fig.6. AS-IV inhibits the activation of mesangial cells and deposition of matrix by inhibiting the ADAM19-Notch pathway.
Fig.7. Inhibiting the ADAM19/Notch signaling pathway suppresses mesangial cell activation and matrix deposition.
Fig.8. Overexpression of ADAM19 activates the Notch signaling pathway and enhances macrophage recruitment.
AS-IV ameliorates IgAN progression by suppressing ADAM19/Notch1/CCL2 signaling-mediated mesangial activation and reprogramming M2 macrophages. These findings highlight AS-IV as a novel natural therapeutic agent targeting renal fibrosis and immune dysregulation in IgAN.
