Modified Huangqi Chifeng decoction alleviates IgA nephropathy inflammation and renal fibrosis via miR-146a/TLR4/NF-κB signaling modulation

Abstract

Background Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide and a leading cause of end-stage renal disease, posing a significant threat to human health. Modified Huangqi Chifeng decoction (MHCD) has shown efficacy in ameliorating IgAN; however, its underlying regulatory mechanisms remain incompletely understood. Objective To evaluate the anti-inflammatory and anti-fibrotic effects of MHCD on IgAN and elucidate its molecular mechanisms through in vivo and in vitro experiments. Methods An IgAN rat model was established. The therapeutic effects of MHCD were assessed by measuring 24-hour urinary protein, Gd-IgA1, serum biochemistry, renal pathological damage, IgA deposition, inflammatory mediators, and fibrosis levels after 8 weeks of MHCD administration. ELISA was used to quantify inflammatory mediators; Western blot and immunohistochemistry were employed to analyze protein expression; PCR was performed to determine miR-146a levels. Subsequently, lipopolysaccharide-stimulated mesangial cells were used in vitro. Mesangial cell proliferation and the expression of TLR4/NF-κB signaling pathway components and downstream inflammatory factors was examined to verify the anti-inflammatory and anti-fibrotic mechanism of MHCD by overexpressing or silencing miR-146a. Results MHCD reduced urinary protein and serum Gd-IgA1 in IgAN rats, and alleviated renal IgA deposition, pathological injury, inflammation and fibrosis. Furthermore, MHCD inhibited renal expression of TLR4, MyD88, NF-κB p65 and NF-κB p-p65, and increased the level of miR-146a. Mechanistically, in vitro experiments demonstrated that MHCD exerted anti-inflammatory and anti-fibrotic effects by upregulating miR-146a and inhibiting the TLR4/NF-κB signaling pathway. Conclusion MHCD alleviates IgA nephropathy inflammation and renal fibrosis partially through upregulating miR-146a and subsequently suppressing the TLR4/NF-κB signaling pathway.