Studies On The Screening Of Aldose Reductase Inhibitors Of Natural Products From Genus Swertia And The Mechanism Of Anti-diabetic Nephropathy

BackgroundDiabetic nephropathy,main causes of death in diabetic patients,is one of the most common diabetes complications.It is proved that the polyol pathway is closely related to the occurrence of diabetic nephropathy.Aldose reductase is the rate-limiting enzyme of the polyol pathway.Therefore,looking for safe and effective aldose reductase inhibitors has become a research hotspot in the development of anti-diabetic nephropathy drugs.MethodsAldose reductase（AR）is a potential target for antidiabetic nephropathy in Swertia plants by establishing a chemical database and combining with target prediction.Firstly,these compounds are docking with aldose reductase.Then,a screening model of aldose reductase inhibitors was established for screening compounds with good docking results in vitro.Finally,the compound with good activity in vitro is further investigate in db/db mice model.ResultsMolecular docking results suggest that most compounds have good docking scores.Enzyme activity screening results also indicate that flavonoids and xanthones have good inhibitory activity on aldose reductase.The IC₅₀ value of demethylbellidifolin on AR could reach 1.29±0.16μM,which is lower than other compounds.In animal experiments,demethylbellidifolin can significantly reduce FBG and enhance the activity of T-AOC and reducing the level of MDA to improve oxidative stress in db/db mice.This compound could improve renal function damage in diabetic mice by reducing Alb,ACR,BUN,Scr,sorbitol levels.Histomorphology reveale that the compound could maintain the structural integrity of the glomerulus and inhibit the thickening of the basement membrane of the glomerulus.Western blot exhibit that AKR1B1,TGF-β1,CollagenⅣare obviously down-regulated,while Nephrin and Podocin are significantly up-regulated in DN mice kidney tissues after treatment with demethylbellidifolin.ConclusionsDemethylbellidifolin has good therapeutic effect on diabetic nephropathy.It can markedly reduce the blood glucose and improve oxidative stress in diabetic mice.The mechanism of demethylbellidifolin against diabetes nephropathy that reduce the activity of aldose reductase and the overexpression of AR in kidney in db/db mice,inhibite the polyol pathway activation and decrease the accumulation of sorbitol.Eventually achieve the purpose of prevent and treat diabetic nephropathy.