Abstract
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 Lep db/db 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+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, 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 via 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.
Highlights
Diabetic nephropathy (DN) is a serious microvascular complication in patients with diabetes mellitus (DM) and is increasingly regarded as an inflammatory process [1,2,3]
Proteinuria or albuminuria is a clinical risk of the onset and development of diabetic nephropathy (DN) [22, 23]
The results of this present study showed that Hyperoside (HPS) dramatically attenuated albuminuria, which is usually accompanied by dyslipidemia and obesity in db/db mice
Summary
Diabetic nephropathy (DN) is a serious microvascular complication in patients with diabetes mellitus (DM) and is increasingly regarded as an inflammatory process [1,2,3]. Macrophages are important cells involved in the initiation of inflammatory responses and play a critical role in the pathogenesis of DN by secreting various proinflammatory mediators. They can differentiate into proinflammatory M1 macrophages through the classical activation and antiinflammatory M2 macrophages via the alternative activation [4]. Maintaining the M1/M2, Th1/Th2 and Th17/Treg immune balances can reduce the production of proinflammatory cytokines and improve DN [7]. We hypothesized that the imbalance in both innate (M1/M2) and adaptive immunities (Th1/Th2 and Th17/Treg) could play a crucial role in the pathogenesis of DN, while rebalancing these immune responses might represent a novel approach for the treatment of DN
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