| The morbidity of chronic kidney disease(CKD)shows a clear rising trend along with population aging in the world,and the increase of hypertensive,diabetic,obesity and other lifestyle diseases.Now,CKD has become a worldwide public health problem.Due to the poor prognosis and the high cost of treatment,the study on pathogenesis of CKD,and its prevention and intervention measures,has become one of the research focuses in global.Two important features of CKD,inflammation and oxidative stress,which are inseparably linked as each begets and amplifies the other,and can drive the development and progression of CKD and lead to cardiovascular and other body system complications.Thus,medicines,which have anti-inflammation and anti-oxidative effects,can be used as a potential option for the treatment of CKD.Salvianolic acid A(SAA)is a water-soluble minor phenolic carboxylic acid extracted from the root of Salviae Miltiorrhizae Bunge(Danshen).SAA exhibits a variety of pharmacological activities,such as anti-inflammation,anti-oxidative,anti-thrombotic,anti-fibrotic,anti-diabetic,neuroprotective,as well as protection from myocardial ischemia and other diseases.SAA has been reported to attenuate inflammation through inhibition of the secretion and expression of inflammatory mediators in inflammatory cell model and protect against oxidative stress via activating the Nrf2/HO-1 signaling pathway in oxidative stress cell model.Furthermore,SAA has shown renal protective effects in doxorubicin-induced nephropathy.So,SAA could be a potential medicine for the treatment of CKD through its anti-inflammation and anti-oxidative effects.However,there has been limited research regarding the effects of SAA and underlying mechanisms in CKD.Here,we examined the effects and molecular mechanisms of SAA in an established animal model of 5/6 nephrectomized rats(5/6Nx rats,an experimental model of CKD)and in LPS-induced HK-2 cells in vitro(a recognized in vitro inflammatory model)or H2O2-induced HK-2 cells in vitro(a recognized in vitro oxidative stress model).After the 5/6 nephrectomy,the rats were randomly divided into four groups:5/6Nx rats(model group),SAA(2.5,5,10 mg·kg-1·d-1,ip).10 rats which were subjected to a sham operation were served as a control group.After 28 days of treatment,the rat samples were collected.1.Firstly,biochemical parameters were measured using commercial kits in 5/6Nx rats.The results of biochemical analysis showed that SAA dose-dependently lowered the levels of urine protein,blood urea nitrogen(BUN),serum creatinine(SCr),plasma total cholesterol(TC)and plasma triglycerides(TG),which indicates that SAA have improving effects of on CKD.Secondly,histological examination revealed that SAA dose-dependently attenuated renal pathological lesions,evidenced by reduced renal tubulointerstitial fibrosis through decreasing the expression levels of TGF-β1 and α-SMA in 5/6Nx rats.2.Given the key role of inflammation in the progression of CKD,the corresponding inflammatory signaling pathways were detected in the kidney of 5/6Nx rats.The results of IHC,ELISA and western blot demonstrated that SAA dose-dependently inhibited the activation of NF-κB and p38 MAPK signaling pathways,subsequently attenuating the secretion of TNF-α and IL-1β and inhibiting the expression of MCP-1,ICAM-1 and VCAM-1 in kidneys of 5/6Nx rats,which suggests that SAA could significantly inhibit the inflammation of CKD.The above results were consistent with those obtained in LPS-induced HK-2 cells in vitro(a recognized in vitro inflammatory model).3.Oxidative stress,another important factor in the progression of CKD,was examined in 5/6Nx rats.Firstly,oxidative stress-related parameters were detected through biochemical and western blot analysis in 5/6Nx rats.The results showed that SAA dose-dependently increased the activities of total superoxide dismutase(T-SOD),glutathione peroxidase(GPx),catalase(CAT)and decreased the levels of malondialdehyde(MDA),reactive oxygen species(ROS)and NADPH oxidases 4(NOX-4)in 5/6Nx rats.Secondly,the corresponding oxidative stress signaling pathways were detected.The results of western blot,demonstrated that SAA dose-dependently enhanced the activation of Akt/GSK-3β/Nrf2 signaling pathway,subsequently increasing the expression of HO-1 in kidney of 5/6Nx rats.The above results,which suggests that SAA could significantly inhibit the oxidative stress of CKD,were consistent with those obtained in H2O2-induced HK-2 cells in vitro(a recognized in vitro oxidative stress model).4.Furthermore,MLS85(an inhibitor of Nrf2)significantly enhances the activation of the NF-κB signaling pathway and QNZ(an inhibitor of NF-κB)significantly enhances the activation of the Nrf2 signaling pathway in HK-2 cells,which shows reciprocal repression between these two signaling pathways.In conclusion,the results demonstrated that SAA effectively attenuates kidney injury of CKD,which can be attributed to its anti-inflammatory and anti-oxidative activities through inhibition of the activation of the NF-κB and p38 MAPK signaling pathways,and activating the Akt/GSK-3β/Nrf2 signaling pathway. |
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