Febuxostat Attenuates ER Stress Mediated Kidney Injury In A Rat Model Of Hyperuricemic Nephropathy

Background: Hyperuricemia is an independent risk factor for the onset and progression of chronic kidney disease(CKD).Hyperuricemia contributes to kidney tubular injury and kidney fibrosis.However,the underlying mechanism remains unclear.The relationship between ER stress and Hyperuricemic Nephropathy(HN)has not been fully clarified yet.Now,HN were historically regarded with little interest.So it is crucial to explore the mechanism of HN and find a new therapy for HN.Febuxostat,a new selective inhibitor of xanthine oxidase(XO),has been widely used for the treatment of hyperuricemia.So we hypothesis that febuxostat exerts protective effect on HN via inhibiting ER stress.Objectives: We are aimed at examining the role of RTN1 A,a novel endoplasmic reticulum(ER)-associated protein and ER stress in hyperuricemic nephropathy and explored the renal protective effects of febuxostat in HN rat kidneys.To further confirm the direct role of Febuxostat in the regulation of ER stress,we performed in vitro study in rat renal tubular epithelial cells.We try to find a new therapy for HN through exploring the renoprotecive mechanism of febuxostat.Methods: 1.The expression of RTN1 A and ER stress markers in human kidney biopsies of HN patients was detected.2.The kidney injury of HN rats in different periods were detected in order to explore the grogression of HN.3.After treating HN rats with febuxostat,the effects of febuxostat on kidney injury,ER stress and apoptosis in HN rats were determined.4.In vitro,uric acid induces ER stress and apoptosis in rat renal tubular epithelial cells(NRK-52E),which were pretreated with febuxostat.The effects of febuxostat on ER stress and apoptosis in NRK-52 E were detected.Results: 1.We first found the expression of RTN1 A and ER stress markers was significantly increased in kidney biopsies of hyperuricemia patients with kidney injury.2.In a rat model of hyperuricemic nephropathy(HN)established by oral administration of a mixture of adenine and potassium oxonate,increased expression of RTN1 A and ER stress was shown in tubular and interstitial compartment of rat kidneys.3.Treatment of Febuxostat,a new selective inhibitor of xanthine oxidase(XO),not only attenuated renal tubular injury and tubulointerstitial fibrosis,but also reduced uric acid crystals deposition in HN rat kidneys.4.Febuxostat reduced ER stress and apoptosis in uric acid treated tubular epithelial cells.Conclusion: RTN1 A and ER stress mediate tubular cell injury and kidney fibrosis in HN.Urate-lowering therapy(ULT)with Febuxostat attenuates renal tubular injury of HN rats,reduces the tubular cell apoptosis in vitro and slows down the progression of HN.Febuxostat plays a therapeutic role in HN maybe by inhibiting ER stress and the related apoptosis signaling pathway.This study further explored the role of ER stress in HN and provide a new therapy for hyperuricemia-induced kidney injury.