Abstract
Paeoniflorin (PF) is the primary component of total glucosides of paeony (TGP). It exerts multiple effects, including immunoregulatory and anti-inflammatory effects. Our previous study has found that PF has a remarkable renal-protective effect in diabetic mice, but exact mechanism has not been clarified. This study mainly explores whether PF affects macrophage infiltration and activation in diabetic kidney through TLR4 pathway. Thus, this study was conducted to investigate the effect of PF on a streptozotocin (STZ)-induced experimental DN model. The results suggested that the onset and clinical symptoms of DN in mice were remarkably ameliorated after the administration of PF. Moreover, the number of infiltrating macrophages in the mouse kidneys was also markedly decreased. Instead of inhibiting the activation of macrophages directly, PF could influence macrophages by suppressing iNOS expression as well as the production of TNF-α, IL-1β, and MCP-1 both in vivo and in vitro. These effects might be attributable to the inhibition of the TLR4 signaling pathway. The percentage of M1-phenotype cells as well as the mRNA levels of iNOS, TNF-α, IL-1β, and MCP-1 were downregulated when PF-treated polarized macrophages were cultured under conditions of high glucose (HG) levels. In addition, the expression of TLR4, along with that of downstream signaling molecule proteins, was also reduced. Our study has provided new insights into the potential of PF as a promising therapeutic agent for treating DN and has illustrated the underlying mechanism of PF from a new perspective.
Highlights
Diabetic nephropathy (DN) is a microvascular complication of diabetes
The present study demonstrated that PF intervention and knocking out toll-like receptor 4 (TLR4) can decrease the urine albumin level and ameliorate the kidney/body weight ratio, obstructing the progression of DN
The results of our experiment, which are different from the results reported in Fu et al (2009) for diabetic rats treated with a dose of 5–20 mg/kg, demonstrate that PF has no effect on the blood glucose level
Summary
Diabetic nephropathy (DN) is a microvascular complication of diabetes. Recent research has found that chronic microinflammation plays a vital role in the pathogenesis of DN (Wada and Makino, 2013). Macrophages play a major regulatory role in the inflammation seen in the renal tissue of early-stage DN patients (Klessens et al, 2017). These macrophages can be Abbreviations: BMDM, bone marrow-derived macrophage; HG, high glucose; PF, paeoniflorin; STZ, streptozotocin; TLR4, toll-like receptor 4. Paeoniflorin and Macrophage in DN activated by the abnormally elevated levels of pathogenic factors, such as glucose, AGEs and renin, in the renal environment. After activation, they can secrete inflammatory cytokines or mediators and chemokines and produce ROS (Tesch, 2010; Sasaki et al, 2011; Wu et al, 2011), leading to renal structural destruction and renal functional injury in DN patients. Blocking the macrophage activation pathway may be of great significance in preventing chronic DN-related inflammation
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