| Background and objectivesHyperuricemia(HUA)is a common metabolic disease caused by purine metabolic disorders.Human beings do not have active uricase that metabolizes uric acid efficiently,so the risk of HUA is much higher than that of rodents and other mammals.Studies have confirmed that HUA is an important cause of chronic kidney disease(CKD),which can cause sustained and hidden damage to the kidney.Oxidative stress and inflammation are the key factors leading to the occurrence and progression of renal injury.Uric acid can enter cells and play pro-inflammatory and pro-oxidative roles through a variety of mechanisms,such as promoting the formation of free radicals mediated by peroxynitrite、promoting lipid oxidation、promoting the expression of inflammatory markers.Therefore,it is a scientific and effective way to search for drugs with renal protective effect from the perspective of anti-inflammation and anti-oxidation.HUA can lead to kidney damage,which can also lead to uric acid excretion disorders and aggravate HUA.Thus,a vicious circle of HUA-renal injury-HUA was formed.Protecting the kidneys can therefore break this vicious cycle by lowering blood uric acid levels.Ursolic acid,a pentacyclic triterpenoid compound,exists in natural plants and has a variety of biological effects.Ursolic acid has been widely concerned because of its obvious anti-inflammatory and antioxidant effects.We hypothesized that ursolic acid may protect renal function and delay renal fibrosis by inhibiting inflammation and antioxidant effects.To investigate the renal protective effect of ursolic acid and its possible mechanism,our study was conducted to observe the effects of ursolic acid on renal function,renal histopathology,the expression of silence information regulator 1(SIRT1),endothelial nitric oxide synthase(e NOS),nuclear transcription factor-kappa B(NF-κB)and renal fibrosis renal tissue in rats with uric acid nephropathy.Objects and methods1.32 healthy male Sprague Dawley(SD)rats,aged 6 weeks,were randomly divided into four groups: control group,model group(the model was generated using oxonic acid potassium salt),low-dose ursolic acid treatment group(low-dose group,(the model was generated using oxonic acid potassium salt +10mg/kg/day ursolic acid intervention),high-dose ursolic acid treatment group(high-dose group,(the model was generated using oxonic acid potassium salt +30mg/kg/day ursolic acid intervention).Eight rats in each group.The experiment lasted 12 weeks.The weight of rats was measured regularly every day to calculate the required reagents,and the drugs were administered to their stomachs.Except the control group,each group was given 750mg/kg/day oxonic acid potassium salt intragastrically to induce uric acid nephropathy model until the end of the experiment.From week 7,different doses of ursolic acid were added in the high-dose group and low-dose group respectively on the basis of uric acid nephropathy model.2.Blood uric acid levels were dynamically monitored at 0,3,6,9 and 12 weeks.Blood levels of cystatin C,creatinine and urea nitrogen were dynamically monitored at 0,6 and 12 weeks.At the 12 th week,kidney was taken from rats.Renal tissues were stained with HE,Masson and alpha-smooth Muscle Actin(α-SMA)under light microscopy after immunohistochemistry,to assess pathological changes and fibrosis degree of the kidney.The expression of SIRT1,e NOS and NF-κB in renal tissues were determined by RT-q PCR and Western Blot.Results1.At week 12,the levels of serum uric acid,cystatin C and creatinine in model group were significantly higher than those in control group [(311±81)μmol/L vs.(67±34)μmol/L,(152.00±32.71)ng/ml vs.(61.63±18.37)ng/ml,(68.5±20.32)μmol/L vs.(35.88±10.44)μmol/L,P <0.05],and microscopic examination of renal tissue showed increased cell swelling,inflammatory infiltration and interstitial fibrosis.Compared with the model group,levels of serum uric acid,cystatin C and creatinine were significantly reduced in the high-dose group [(185±48)μmol/L vs.(311±81)μmol/L,(70.75±10.03)ng/ml vs.(152.00±32.71)ng/ml,(39.38±7.84)μmol/L vs.(68.5±20.32)μmol/L,P<0.05],and the pathological injury of kidney was significantly improved.Compared with the high-dose group,levels of the serum uric acid,cystatin C and creatinine in the low-dose group were less effective in improving and delaying renal fibrosis [(261±54)μmol/L vs.(185±48)μmol/L,(95.63±14.55)ng/ml vs.(70.75±10.03)ng/ml,(60.88±17.89)μmol/L vs.(39.38±7.84)μmol/L].There was no significant difference in levels of urea nitrogen among all groups(P>0.05).2.Compared with the control group,the expression of SIRT1 and e NOS in kidney tissue of rats in model group were significantly decreased[(0.28±0.07)vs.(1.02±0.18),(0.28±0.08)vs.(1.03±0.26),P<0.05],and the expression of NF-κB was significantly increased[(1.38±1.23)vs.(0.63±0.19),P<0.05].Compared with the model group,the expression of SIRT1 and e NOS in renal tissue of rats in high-dose group were significantly increased [(1.17±0.33)vs.(0.28±0.07),(0.75±0.15)vs.(0.28±0.08),P<0.05],and the expression of NF-κB was significantly increased[(0.84±0.12)vs.(1.38±1.23),P<0.05].The expression of SIRT1/e NOS/NF-κB in renal tissue of rats in low-dose group were also significantly different from those in model group [(0.64±0.22)vs.(0.28±0.07),(0.47±0.18)vs.(0.28±0.08),(1.28±0.27)vs.(1.38±1.23),P<0.05].However,the differences was smaller than that between the high-dose group and model group.Conclusions1.Ursolic acid can protect the kidney and reduce the level of uric acid in uric acid nephropathy.2.Ursolic acid may play a protective role via SIRT1/e NOS /NF-κB pathways.2.Renal protective effects of ursolic acid may be dose-dependent. |
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