Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus

• Published in: Frontiers in immunology Vol. 12; p. 733808
• Main Authors: Liu, Jialing, Zhang, Yanmei, Sheng, Hongqin, Liang, Chunling, Liu, Huazhen, Moran Guerrero, Jose Alberto, Lu, Zhaoyu, Mao, Wei, Dai, Zhenhua, Liu, Xusheng, Zhang, Lei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 03.12.2021
• Subjects: Animals; Cell Polarity - drug effects; Cells, Cultured; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Type 2 - complications; Diabetic Nephropathies - complications; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - immunology; diabetic nephropathy; Drugs, Chinese Herbal - administration & dosage; hyperoside; Immunology; Macrophage Activation - drug effects; macrophage polarization; Macrophages - immunology; Male; Mice; Mice, Inbred C57BL; Nephritis - complications; Nephritis - drug therapy; Nephritis - immunology; Phytotherapy - methods; Protective Agents - administration & dosage; Quercetin - administration & dosage; Quercetin - analogs & derivatives; renal inflammation; T-Lymphocytes, Regulatory - immunology; Th1 cell; Th2 Cells - immunology; Treatment Outcome; Treg cell; macrophage polarization; hyperoside; Th1 cell; Treg cell; diabetic nephropathy; renal inflammation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.733808

Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80 CD11b CD86 ) to anti-inflammatory M2 ones (F4/80 CD11b CD206 ) and in bone marrow-derived macrophages (BMDMs) , resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4 T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4 T cells while promoting their differentiation into CD4 IL-4 Th2 and CD4 Foxp3 Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN promoting macrophage polarization from an M1 to M2 phenotype and CD4 T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.