Toll-like receptors (TLRs) may be involved in diabetic nephropathy (DN). Paeoniflorin (PF) is an effective Chinese traditional medicine with anti-inflammatory and immunoregulatory effects that may inhibit the TLR2 signaling pathway. In this study, we investigated the effects of PF on the kidneys of mice with streptozotocin-induced type 1 diabetes mellitus using TLR2 knockout mice (TLR2−/−) and wild-type littermates (C57BL/6J-WT). After 12 weeks of intraperitoneal injection of PF at doses of 25, 50, and 100 mg/kg once a day, diabetic mice had significantly reduced albuminuria and attenuated renal histopathology. These changes were associated with substantially alleviated macrophage infiltration and decreased expression of TLR2 signaling pathway biomarkers. These data support a role of TLR2 in promoting inflammation and indicate that the effect of PF is associated with the inhibition of the TLR2 pathway in the kidneys of diabetic mice. PF thus shows therapeutic potential for the prevention and treatment of DN.
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.
Our findings suggested that high glucose activated macrophages mainly in TAK1/MAPKs and TAK1/NF-κB-dependent manners, which lead to the polarization of macrophages towards a pro-inflammatory phenotype, and finally lead to diabetic nephropathy. In sum, the study raises novel data about the molecular mechanisms involved in the high glucose-mediated inflammatory response in macrophages.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.