Oridonin protects against the inflammatory response in diabetic nephropathy by inhibiting the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways.

Inflammation plays a pivotal role in the development and progression of diabetic nephropathy (DN). Oridonin (Ori), a component isolated from Rabdosia rubescens, possesses remarkable anti-inflammatory, immunoregulatory and antitumor properties. However, the renoprotective effects of Ori and the underlying molecular mechanisms have not been explored in DN. In this study, we aimed to investigate the protective effects and potential mechanisms responsible for the anti-inflammatory effects of Ori in diabetes-induced renal injury in vivo and in vitro. Our results showed that Ori significantly attenuated diabetes-induced renal injury and markedly decreased urinary protein excretion levels, serum creatinine concentrations and blood urea nitrogen concentrations in rats. Ori also significantly alleviated infiltration of inflammatory cells (cluster of differentiation (CD)68) in kidney tissues and reduced the levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β and monocyte chemotactic protein 1 (MCP-1), both in vivo and in vitro. TLR4 is a principal mediator of innate immune and inflammatory responses and participates in the development of DN. Our molecular studies indicated that Ori administration significantly down-regulated TLR4 overexpression in DN. Additional studies were conducted to investigate the effect of Ori on the p38-mitogen-activated protein kinase (p38-MAPK) and nuclear factor (NF)-κB pathways. The results showed that Ori inhibited IκBα, p65, and p38 phosphorylation, as well as NF-κB DNA-binding activity. In conclusion, these results demonstrated that Ori exerts protective effects in diabetes-induced renal injury in vivo and in vitro. These effects may be ascribed to its anti-inflammatory and modulatory effects on the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways.

Li J ，Bao L ，Zha D ，Zhang L ，Gao P ，Zhang J ，Wu X ... -  《-》

[Effect and mechanism of Maxing Shigan Decoction on reducing inflammatory response in rats with cough variant asthma via TLR4/MyD88/NF-κB and p38 MAPK signaling pathways].

Fu ZH ，Zhou L ，Nie AZ 《-》

Astragalus Polysaccharide Ameliorates Renal Inflammatory Responses in a Diabetic Nephropathy by Suppressing the TLR4/NF-κB Pathway.

Diabetic nephropathy (DN), as a chronic inflammatory complication of diabetes, is characterized by hyperglycemia, albuminuria and edema, which ultimately becomes the leading cause of end-stage renal disease (ESRD). Astragalus polysaccharide (APS), extracted from the Astragalus membranaceus, was widely used in the treatment of diabetes mellitus. However, the functional roles of APS ameliorate inflammatory responses in DN, which remain poorly understood. Therefore, the purpose of this study was to explore the molecular mechanism of APS on DN in vivo and vitro models. We explored the beneficial effects of APS in streptozotocin (STZ)-induced DN rat model and high glucose (HG)-treated glomerular podocyte model. The fasting blood glucose (FBG) and ratio of kidney weight to body weight were measured after 4 weeks of APS treatment. The renal injury parameters containing serum creatinine (Scr), blood urea nitrogen (BUN) and 24 h urinary protein were evaluated. The renal pathological examination was observed by hematoxylin-eosin (HE) staining. The levels of IL-1β, IL-6 and MCP-1 were evaluated by ELISA assay. The proliferation of podocytes was determined using CCK-8 assay and flow cytometry. qRT-PCR and Western blot analysis were performed to determine the amounts of TLR4/NF-κB-related gene expression. Our results indicated that APS effectively decreased the levels of FBG, BUN, Scr and renal pathological damage when compared with STZ-induced DN model group. Additionally, APS significantly ameliorated renal injury by reducing inflammatory cytokines IL-1β, IL-6, MCP-1 expression and inhibiting the TLR4/NF-κB pathway activity in DN rats. Consistent with the results in vitro, the HG-induced inflammatory response and proliferation of glomerular podocytes were also alleviated through APS administration. We found that APS ameliorated DN renal injury, and the mechanisms perhaps related to relieving inflammatory responses and attenuating the TLR4/NF-κB signaling pathway.

Guo M ，Gao J ，Jiang L ，Dai Y ... -  《-》

Hirudin Protects Against Kidney Damage in Streptozotocin-Induced Diabetic Nephropathy Rats by Inhibiting Inflammation via P38 MAPK/NF-κB Pathway.

Inflammation-induced podocyte apoptosis plays an important role in kidney injury during diabetic nephropathy (DN). Hirudin (HIR), a natural compound extracted from leeches, can inhibit inflammation. However, whether HIR can protect the kidneys against inflammation during DN is unknown. In the present study, we aimed to study the effects of HIR on kidney damage in a DN rat model and explore its anti-inflammatory properties. A streptozotocin-induced DN rat model was generated, and HIR was administered subcutaneously. Immortal podocytes and primary peritoneal macrophages were used for vitro studies. Hematoxylin and eosin staining was used to evaluate renal pathological changes; quantitative polymerase chain reaction and immunoblotting were used to detect gene expression; and TUNEL staining was used to detect apoptotic cells. Our results showed that HIR protected against renal injury, as indicated by kidney weight/body weight, serum creatinine, renal pathological changes, blood urea nitrogen, and detection of urine proteins. Notably, HIR treatment reduced macrophage infiltration, pro-inflammatory cytokine expression, and podocyte apoptosis in the kidney tissues of DN rats. In vitro, high glucose (HG) induced the activation of M1 macrophages, which was accompanied by increased podocyte apoptosis. HIR could decrease HG-induced podocyte apoptosis and suppress pro-inflammatory cytokine expression in podocytes in vitro. This was achieved via inhibition of p38 MAPK/NF-κB activation in renal tissues and podocytes. HIR could inhibit inflammation via the p38 MAPK/NF-κB pathway, prevent podocyte apoptosis, and protect against kidney damage in a DN rat model.

Han J ，Pang X ，Zhang Y ，Peng Z ，Shi X ，Xing Y ... -  《-》

Oridonin ameliorates renal fibrosis in diabetic nephropathy by inhibiting the Wnt/β-catenin signaling pathway.

Li J ，Shu L ，Jiang Q ，Feng B ，Bi Z ，Zhu G ，Zhang Y ，Li X ，Wu J ... -  《-》