Study on the mechanism of Huangqi Dongchong Xia herbal medicine in treating IgA nephropathy based on network pharmacology, molecular docking, and rat experiments
IgA nephropathy (IgAN) is an autoimmune disease characterized by the deposition of immune complex IgA in the mesangial area of the glomerulus, often accompanied by endothelial hyperplasia and podocyte damage. In China, the incidence rate is high, accounting for 32%~54% of primary glomerulonephritis. About 40% of patients will enter end-stage renal disease in about 20 years. At present, treatment mainly includes controlling blood pressure, reducing urinary protein, hormones, and immunosuppressants. Although they can delay disease progression, the adverse reactions of related drugs also limit the efficacy. Therefore, actively exploring ideal therapeutic drugs for IgAN and protecting kidney function has become an urgent clinical problem to be solved.
Traditional Chinese medicine has a long history of treating IgAN, which can improve efficacy and protect kidney function. However, the current research perspective is still single, and the mechanism of traditional Chinese medicine in treating IgAN has not been systematically demonstrated. Professor Chen Bangming is the disciplinary leader of Jiangxi Provincial Clinical Research Center for Traditional Chinese Medicine Kidney Disease, a renowned traditional Chinese medicine practitioner at the provincial level, and has gathered the strengths of various schools. He believes that the pathogenesis of this disease is the disturbance of the kidneys by the deficiency of positive energy and the suppression of evil energy. In response to deficiency, proficient in using Huangqi winter worm summer herbs to nourish the lungs, spleen, and kidneys. Huangqi is sweet and warm, nourishing kidney qi, strengthening spleen and reducing swelling. It has the effects of regulating immunity, reducing urinary protein, and protecting kidney function. It can inhibit renal fibrosis by upregulating hepatocyte growth factor (HGF) and downregulating transforming growth factor – β 1 (TGF – β 1), increase IgAN peripheral blood B lymphocytes, and reduce glycosylation levels. Cordyceps sinensis has a sweet and mild taste, which can nourish the lungs and kidneys, inhibit the proliferation of VEGF and IgA mesangial cells, and repair kidney damage; Modern research has confirmed that both drugs have the effect of regulating immunity and inhibiting mesangial proliferation, and their combination can synergistically enhance efficacy. Therefore, this article is based on the strategy of discovering drug action mechanisms using network methods, aiming to discover and study the mechanism of action of Huangqi Dongchong Xia herbal medicine from a systematic and molecular perspective, which is similar to the overall concept of traditional Chinese medicine and the principle of syndrome differentiation and treatment. Therefore, the application of network pharmacology technology can predict the integrated mechanism of Huangqi Dongchong Xia herbal medicine in treating IgAN with multiple components, targets, and diseases, and provide direction for future experimental verification.

 

Based on its clinical characteristics, this disease belongs to the categories of traditional Chinese medicine, such as hematuria, cloudy urine, and slow kidney wind. Traditional Chinese Medicine believes that this disease is mostly caused by spleen and kidney deficiency, with dampness and turbidity accumulating internally, and long-term accumulation of blood stasis as the standard; According to the evidence obtained from literature review, traditional Chinese medicine treatment for IgAN mainly focuses on nourishing the lungs, spleen, and kidneys, while promoting blood circulation and removing blood stasis runs through the entire process. Director Chen Bangming believes that the deposition of IgAN immune complexes belongs to the traditional Chinese medicine “micro dry blood”, with “stasis and turbidity” as its core pathogenesis. Huangqi Dongchong Xia herbal medicine can not only nourish the lungs, spleen and kidneys, but also inhibit renal fibrosis, remove stubborn blood stasis in the kidneys, and delay the progression of renal function.

This study screened 37 bioactive compounds, and the key active compounds identified from the construction of the active compound target interaction network were arachidonic acid, β – sitosterol, isorhamnetin, kaempferol, and quercetin. Arachidonic acid is an n-6 essential fatty acid that can regulate human immune function, inhibit platelet aggregation, anticoagulate, suppress renal fibrosis, and protect podocytes; β – sitosterol has significant antioxidant effects by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). It can also reduce the levels of tumor necrosis factor alpha (TNF – α) and IL-6, inhibit TLR receptor signaling, and exert anti-inflammatory effects. Isorhamnetin inhibits fibrosis by acting on the TGF – β 1/Smad3 and TGF – β 1/p38MAPK pathways to suppress extracellular matrix formation. Shanna phenol can significantly reduce oxidative stress and lipid peroxidation by inhibiting the ASK1/MAPK pathway; Inhibit the release of inflammatory factors through the NF – κ B signaling pathway. Quercetin is a flavonoid compound that has antioxidant, anti-inflammatory, metabolic toxin reducing, and kidney protective effects. In summary, the main active ingredients of Huangqi Cordyceps sinensis may exert therapeutic effects on IgAN through anti fibrosis, antioxidant, immune regulation, and inflammation inhibition.
Based on the Huangqi Cordyceps active ingredient IgAN target interaction network, key targets such as VEGFA, HIF1A, NOS3, CASP3 were discovered. Research has shown that VEGFA is a subtype of VEGF that promotes interstitial fibrosis, is highly expressed in the glomerular and tubular epithelial cells of IgAN patients, can disrupt the renal barrier, exacerbate proteinuria, and independently predict clinical outcomes in IgAN patients. The deposition of immune complexes in the mesangial area stimulates endothelial cells to secrete a large amount of VEGF, which binds to receptors and induces angiogenesis. At the same time, by stimulating oxidative stress and inflammation, it further exacerbates mesangial proliferation, increases extracellular matrix, and leads to glomerulosclerosis. HIF1A can promote renal fibrosis by activating Notch-1 during transcription and post transcription. NOS3 can reduce SOD levels and exert antioxidant and anti-inflammatory effects. Caspase-3 is the main effector factor in the process of cell apoptosis, mediating apoptosis related to renal inflammatory response and fibrosis formation.
According to the KEGG database, the analysis of the annotation of the signal pathway shows that the bioactive components of Astragalus Cordyceps may act on the lipid and atherosclerosis signal pathway, AGE-RAGE signal pathway, fluid shear stress and atherosclerosis pathway, PI3K Akt signal pathway, etc. Lipid and atherosclerosis are the main factors of kidney disease with cardiovascular risk. Fluid shear stress and atherosclerosis pathway are the main ways to inhibit inflammation, vasodilation and anti atherosclerosis. AGE/RAGE can promote the release of inflammatory cytokines and the generation of extracellular matrix, leading to glomerular hypertrophy and glomerulosclerosis. It can also crosslink with collagen and mediate protein deposition. The PI3K Akt signaling pathway can mediate renal inflammation and cell apoptosis.
To sum up, this study shows that Astragalus Cordyceps inhibits multiple pathological links such as fibrosis, anti-inflammatory and oxidative stress by acting on key targets such as VEGFA, HIF1A, NOS3, CASP3 and multiple signal pathways such as lipid and atherosclerosis signal pathway, AGE-RAGE signal pathway, fluid shear stress and atherosclerosis pathway, PI3K-Akt signal pathway, so as to play an integrated regulatory effect of multiple links and targets. Molecular docking also confirmed strong binding activity between the aforementioned components and targets. At the same time, the IgA rat model was combined to validate the strong binding activity of VEGFA targets. The results showed that Huangqi Dongchong Xia herbal medicine could significantly reduce the urinary protein and VEGFA content of the model group rats, confirming that Huangqi Dongchong Xia herbal medicine can delay the progression of IgA nephropathy through multiple molecular targets and pathways.