Study On The Effect And Mechanism Of Diosmetin Against Renal Damage In Hyperuricemia

Long-term hyperuricemia can cause renal endothelial dysfunction,activate the Renin-Angiotensin System(RAS),inflammatory response,oxidative stress,etc.Clinically,it is mainly characterized by acute uric acid nephropathy and chronic uric acid kidney disease and uric acid kidney stones.Nowadays,allopurinol,an inhibitor of uric acid production,and benzbromarone,a uric acid excretion promoting drug,are mainly used in the treatment of renal damage caused by hyperuricemia.Although these drugs have certain curative effects on the diseases,they have many side effects and weak renal protection,the development of new anti-hyperuricemia renal damage drugs has become a hot spot.Diosmetin is a kind of flavonoid compound,which has anti-inflammatory,anti-oxidant,renal protection and other pharmacological effects,which has the potential to develop as an anti-hyperuricemia renal damage drug.Therefore,on the basis of establishing a stable mouse model of hyperuricemia renal damage in vivo,this study explored the protective effect and mechanism of diosmetin on hyperuricemia kidney damage in vivo,and the effect of diosmetin on xanthine oxidase activity in vitro.(1)Mouse models of hyperuricemia with renal injury were establshed by administering one,two or three of five drugs,namely potassium oxonate,hypoxanthine,adenine,ethambutol and yeast extract,at different modeling time by using different modeling dose and modeling method.The changes of uric acid(UA),blood urea nitrogen(BUN)and creatinine(Cr)in sera,and xanthine oxidase(XOD)and adenosine deaminase activity(ADA)in liver were determined.Pathological changes in kidney and the variations in weight of each group were analyzed.The results showed that compared with the normal group,in the 14-day combination medication group of yeast extract and potassium oxonate,the UA,BUN and Cr levels all significantly increased(P<0.01),and renal tubular epithelial cells fell off,and eosinophilic insoluble proteins were visible in some of the proximal tubules,and there was no significant decrease on the body weight of mice.Therefore,it was feasible that mouse model with hyperuricemic renal damage was induced by the combination medication of yeast extract and potassium oxonate.(2)The mouse model with hyperuricemic renal damage was established by the combination medication of yeast extract and potassium oxonate,then effect and mechanism of diosmetin or diosmetin combined with allopurinol on the mouse model with hyperuricemic renal damage were investigated by intraperitoneal injection or intragastric administration.The results showed that compared with the model group,in diosmetin administered groups,the serum UA level and renal MDA level significantly decreased(P<0.05 or P<0.01)and the activities of SOD,GSH-PX and CAT in kidney significantly increased(P<0.05 or P<0.01),the total score of renal pathological tissue damage and the expression of IL-1? and NLRP3 in kidney of mice significantly decreased(P<0.01),while the BUN level,the Cr level and renal index significantly increased(P<0.05 or P<0.01),spleen index significantly increased(P<0.05 or P<0.01)in diosemtin groups by intraperitoneal injection;The UA,BUN and Cr levels,renal index,the total score of renal pathological tissue damage and the expression of IL-1? and NLRP3 in kidney of mice significantly decreased(P<0.01),the activities of GSH-PX and CAT in kidney significantly increased(P<0.05 or P<0.01)in the combination medication of diosmetin and allopurinol group.(3)The effect of diosmtin on XOD activity in vitro was investigated by high throughput screening.The results showed that the inhibitory effect of diosmtin on XOD activity was dose-dependent,its IC50 value was 5.08?mol/L.Meanwhile,diosmtin could competitively inhibit XOD activity.In conclusion,diosmtin reduced uric acid production by competitive inhibition of XOD activity in vitro,and protected the kidneys of mice with hyperuricemia renal damage through anti-inflammatory and anti-oxidative effects in vivo.