Pharmacological Inhibition Of Autophagy By 3-MA Attenuates Hyperuricemic Nephropathy

With the changes of people’s diet and lifestyle,the incidence of hyperuricemia is increasing year by year.At the same time,hyperuricemia is common in patients with chronic kidney disease,and hyperuricemia is closely related to the high mortality rate of patients with chronic kidney disease.Autophagy has been identified as a cellular process of bulk degradation of cytoplasmic components and its persistent activation is critically involved in the renal damage induced by ureteral obstruction.However,the role and underlying mechanisms of autophagy in hyperuricemic nephropathy（HN）remain unknown.In this study,t he expressions of autophagy markers（beclin-1、LC3b、Atg7）and inflammatory markers MCP-1 were observed in renal biopsy specimens of different pathological types in our hospital.The control group is normal renal tissue adjacent to renal carcinoma in age and sex matched.The expression of these markers were mainly observed in tubulointerstitial,indicating that autophagy and inflammation existed in these kidney diseases.In the present study,we observed that inhibition of autophagy by 3-methyladenine（3-MA）abolished uric acid-induced differentiation of renal fibroblasts to myofibroblasts and activation of transforming growth factor-β1（TGF-β1）,epidermal growth factor receptor（EGFR）,and Wnt signaling pathways in cultured renal interstitial fibroblasts.Treatment with 3-MA also abrogated the development of HN in vivo as evidenced by improving renal function,preserving renal tissue architecture,reducing the number of autophagic vacuoles,and decreasing microalbuminuria.Moreover,3-MA was effective in attenuating renal deposition of extracellular matrix（ECM）proteins and expression ofα-smooth muscle actin（α-SMA）and reducing renal epithelial cells arrested at the G₂/M phase of cell cycle.Injury to the kidney resulted in increased expression of TGF-β1 and TGFβreceptor I,phosphorylation of Smad3 and TGF-β-activated kinase 1（TAK1）,and activation of multiple cell signaling pathways associated with renal fibrogenesis,including Wnt,Notch,EGFR,and nuclear factor-κB（NF-κB）.3-MA treatment remarkably inhibited all these responses.In addition,3-MA effectively suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney.Collectively,these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts and development of renal fibrosis and suggest that inhibition of autophagy may represent a potential therapeutic strategy for HN.