Drug Design, Development and Therapy (Mar 2022)
The Astragaloside IV Derivative LS-102 Ameliorates Obesity-Related Nephropathy
Abstract
Ziyu Li,1 Wei Yang,1 Yong Yang,1 Jianbo Wu,2 Pei Luo,3 Yong Liu1,4,5 1Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3State Key Laboratories for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, People’s Republic of China; 4Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, People’s Republic of China; 5Medical Equipment Department, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Yong Liu, Email [email protected]: Astragaloside IV is the most important bioactive component of Radix Astragali. Previous studies have shown that astragaloside IV plays an important role in the control of early- and mid-stage diabetes and late diabetic nephropathy. However, it is disappointing that the in vivo solubility of astragaloside IV and its bioavailability after oral administration are very low. We recently obtained a new water-soluble derivative of astragaloside IV-astragaloside formic acid (LS-102), which has higher bioavailability than the parent compound. In our previous study, we found that there was a significant inflammatory response in the perirenal adipose tissue of mice with obesity-related nephropathy induced by a high-fat diet (HFD), which was related to macrophage infiltration. We hypothesized that in model mice with obesity-related nephropathy, LS-102 effectively regulated the inflammatory response and pathological changes in obesity-related nephropathy through macrophages in perirenal adipose tissue. If this hypothesis is true, the effects of LS-102 and astragaloside IV on TGF-β 1/Smad signal transduction will be further investigated.Methods: In this study, adipose stem cells and an HFD-induced obesity-related nephropathy mouse model were used to observe the regulatory effect of LS-102 on perirenal fat inflammation and the mechanism. Adipose mesenchymal stem cells were extracted from mice that were fed a normal diet and those with obesity-related nephropathy. The effects of LS-102 on the proliferation of two kinds of cells were measured by the CCK-8 method. The levels of tumor necrosis factor-α (TNF-a) and plasminogen activator inhibitor-1 (PAI-1) were measured by ELISA. Obesity-related nephropathy mice were randomly divided into five groups: the HFD group, the LAS group (HFD+low concentration of astragaloside IV [10 mg/kg], intragastrically [ig]), the HAS group (HFD+high concentration of astragaloside IV [40 mg/kg], ig), the L102 group (HFD+low concentration of LS-102 [10 mg/kg], ig) and the H102 group (HFD+high concentration of LS-102 [40 mg/kg], ig). Body weight was measured, and the levels of serum glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), serum creatinine (Crea) and blood urea were measured. The kidneys were stained with HE, PAS and Masson’s trichrome. Perirenal adipose tissue was harvested to examine the expression of CD68, LCA, CD11C, TNF-a, TGF-β 1, Fn1, Smad2, Smad3, Smad4, and Smad7 by immunohistochemical staining, and F4/80 was examined by immunofluorescence staining.Results: LS-102 significantly inhibited the in vitro secretion of TNF-a and PAI-1 by adipose stem cells in a concentration-dependent manner (P 0.05).Conclusion: Astragaloside IV and LS-102 improved the inflammatory reaction in perirenal adipose tissue and renal pathological changes in obesity-related nephropathy model mice and inhibited the TGF-β 1/Smad signaling cascade. At the same concentration, the effect of LS-102 was better than that of astragaloside IV. These results suggest that LS-102 has a better protective effect against obesity-related nephropathy. LS-102 may be a new type of traditional Chinese medicine for the clinical treatment of obesity and its related metabolic diseases.Keywords: LS-102, obesity-related nephropathy, inflammation, macrophages, PAI-1, TGF-β 1, Smads
