Abstract
Nephrotic syndrome (NS) is a clinical syndrome resulting from abnormal glomerular permeability, mainly manifesting as edema and proteinuria. Qingrekasen granule (QRKSG), a Chinese Uyghur folk medicine, is a single-flavor preparation made from chicory (Cichorium intybus L.), widely used in treating dysuria and edema. Chicory, the main component in QRKSG, effectively treats edema and protects kidneys. However, the active components in QRKSG and its underlying mechanism for treating NS remain unclear. This study explored the specific mechanism and composition of QRKSG on an NS rat model using integrated metabolomics and network pharmacology. First, metabolomics explored the relevant metabolic pathways impacted by QRKSG in the treatment of NS. Secondly, network pharmacology further explored the possible metabolite targets. Afterward, a comprehensive network was constructed using the results from the network pharmacology and metabolomics analysis. Finally, the interactions between the active components and targets were predicted by molecular docking, and the differential expression levels of the target protein were verified by Western blotting. The metabolomics results showed “D-Glutamine and D-glutamate metabolism” and “Alanine, aspartate, and glutamate metabolism” as the main targeted metabolic pathways for treating NS in rats. AKT1, BCL2L1, CASP3, and MTOR were the core QRKSG targets in the treatment of NS. Molecular docking revealed that these core targets have a strong affinity for flavonoids, terpenoids, and phenolic acids. Moreover, the expression levels of p-PI3K, p-AKT1, p-mTOR, and CASP3 in the QRKSG group significantly decreased, while BCL2L1 increased compared to the model group. These findings established the underlying mechanism of QRKSG, such as promoting autophagy and anti-apoptosis through the expression of AKT1, CASP3, BCL2L1, and mTOR to protect podocytes and maintain renal tubular function.
Highlights
Nephrotic syndrome (NS) is a clinical condition caused by inflammation, oxidative stress, immune injury, and podocyte damage in the kidney (Imig and Ryan, 2013; Zhang et al, 2018)
Qingrekasen granule (QRKSG) treatment reduced the levels of TG, BUN, total cholesterol (TC), and Cr in the serum, while the level of ALB and total protein (TP) increased (Figure 2)
The smaller the absolute value of the docking score between the compound and the target, the worse their binding activity (Gupta et al, 2018). These findings revealed that AKT1, CASP3, and mammalian target of rapamycin (mTOR) targets have a strong affinity for most compounds, including flavonoids, terpenoids, and phenolic acids
Summary
Nephrotic syndrome (NS) is a clinical condition caused by inflammation, oxidative stress, immune injury, and podocyte damage in the kidney (Imig and Ryan, 2013; Zhang et al, 2018). Many patients with kidney diseases have resorted to traditional Chinese medicines (TCM) (Zhao et al, 2015), whose biological activity and therapeutic effects are proven in vitro and animal experiments (Fang et al, 2013; Zhang et al, 2014). Chicory (Cichorium intybus L.), is a medicinal plant widely distributed in Europe, America, and Asia, and the main components of Qingrekasen Granule (QRKSG), listed in the Pharmacopoeia of the People’s Republic of China (2020 edition). The sesquiterpene lactones 8-Deoxylactucin, lactucin, and lactucopicrin in chicory extract inhibit the production of prostaglandin E2 (PGE2) and COX-2 protein expression (Cavin et al, 2005), reducing incidences of edema and inflammatory pain (Wesolowska et al, 2006). QRKSG is a granule made from chicory, and is approved by the China Food and Drug Administration, approval number The functional mechanisms and value of QRKSG in NS are unknown
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