Mechanism Of Multi-glycoside Of Tripterygium Wilfordii Hook.f. For Ameliorating Glomerular Inflammatory Injury Through Regulating P38MAPK Signaling Pathway In Diabetic Nephropathy Rat

[Background/Aims] This thesis is made up of3parts. The first, we reviewed the general situation about the treatment of diabetic nephropathy (DN) in Traditional Chinese Medicine (TCM). DN belongs to a category of subdue thirsty disease (xiaoke) related nephropathy. The basic pathogenesis of DN is qi-yin deficiency and blood stasis. The syndrome differentiation is classified as original syndrome and superficial syndrome. Original syndrome includes yin-deficiency and dryness-heat syndrome, qi-yin deficiency syndrome, spleen-kidney deficiency syndrome, and yin-yang deficiency syndrome. Superficial syndrome contains dampness syndrome, stasis syndrome, and phlegm and stasis syndrome. In clinic, a lot of single Chinese herbal medicines (CHM), CHM compounds, and empirical prescriptions from prominent TCM doctors could improve the clinical symptoms of patients with DN in different degrees, through reducing urinary albumin (UAlb) and improving renal function. The second, we summarized the mechanism of renal inflammatory-related p38mitogen-activated protein kinase (MAPK) signaling pathway in DN and the interventional effects of CHM. In the process of DN, inflammatory-related p38MAPK signaling pathway has a close relationship with renal injury. On the one hand, many factors in the upstream including hyperglycemia, abnormal hemodynamics, oxidative stress, and pro-inflammatory cytokines could activate p38MAPK signaling pathway. On the other hand, the activated p38MAPK signaling pathway could lead to renal damage via activating inflammatory cells, inducing the expression of inflammatory mediators, and intervening cytokines production. CHM could intervene p38MAPK signaling pathway through multi-ways, including inhibiting inflammatory cytokines expression, regulating phosphorylated p38(p-p38MAPK) expression, and reducing fibrogenic factors expression. At last, as a focal point in this thesis, by means of DN model rats, we clarified the characteristics of glomerular inflammatory damage in the kidney in vivo, and that, demonstrated the effect and mechanism of multi-glycoside of Tripterygium wilfordii Hook. f.(GTW) on improving glomerular inflammatory lesion in rats with DN.[Methods] DN model was induced by unilateral nephrectomy and intraperitoneal injection of streptozotocin(STZ)(35mg·kg-1). In experiment1, the rats were randomly divided into2groups:the normal group and model groupn (n=5). After the model was successfully established, the rats in2groups were intervened without any drug. All rats were killed8weeks later and renal tissues were collected. The infiltration of glomerular macrophages, the expressions of interleukin(IL)-1β, tumor necrosis factor (TNF)-α, p38MAPK, p-p38MAPK, and transforming growth factor (TGF)-β1, as well as the characteristics of glomerular morphology were examined, respectively. In experiment2, the rats were randomly divided into3groups:the sham-operated group, vehicle group, and GTW-treated group (n=5).After the model was successfully established, the rats in GTW-treated group and vehicle group were daily oral administrated with GTW suspension (50mg·kg-1·d-1) or distilled water2mL, and the rats in the sham-operated group were also administrated with distilled water2mL for8weeks. From the beginning of the administration, all rats were killed8weeks later. Blood and renal tissues were collected, UAlb, renal function, glomerular morphology characteristics, glomerular macrophages infiltration, inflammatory cytokines expression, and the key molecules expression in p38MAPK signaling pathway were examined, respectively.[Results] In experiment1, the infiltration of glomerular macrophages was increased, the protein expressions of IL-1β, TNF-α, p-p38MAPK, and TGF-β1were up-regulated, as well as the typical glomerulosclerosis was showed up in DN model rats.In experiment2, GTW could not only improve the general state of health, body weight, kidney weight, and kidney weight/body weight but also ameliorate UAlb, glomerulosclerosis, the infiltration of glomerular macrophage ED1+, the protein expressions of ED1+, IL-1β, TNF-α, p-p38MAPK, and TGF-β1in the kidney in DN model rats.[Conclusion] By means of DN model rats, we demonstrated that①The activation of p38MAPK signaling pathway is a characteristic of glomerular inflammatory injury in DN;②GTW had the protective effect on renal inflammatory damage via inhibiting inflammatory cell infiltration and inflammatory cytokines expression in vivo;③GTW could improve renal inflammatory lesion by the way of intervening the transduction of p38MAPK signaling pathway in the kidney through down-regulating the expressions of the key signaling molecules in p38MAPK pathway,such as TGF-β1and p-p38MAPK.