Uric Acid Promotes The Progression Of Renal Damage In Diabetic Patients And ROS-mediated Activation Of NLRP3 Inflammasome Is Involved In The Mechanism Of Uric Acid Damage To Renal Tubular Epithelial Cells

Aims: Serum uric acid(UA)increases in patients with kidney disease due to the impaired UA clearance.The present study sought to evaluate the association between UA/creatinine ratio(UA/Cr)and renal disease progression in patients with type 2 diabetes mellitus(T2DM)in Chinese communities.Methods: In the present retrospective longitudinal study,3432 Chinese T2 DM patients recruited from 11 community healthcare centers in Nanjing,China were included.Renal disease progression was defined as the occurrence of estimated glomerular filtration rate(eGFR)< 15 mL/min/1.73 m2 or doubling of baseline serum creatinine level.Cox regression analysis was used to estimate the association between UA/Cr and renal disease progression.Results: During a median follow-up of 30 months,58(1.70%)patients experienced progression of renal disease,which was more common among those with older ages,longer diabetes duration,and higher baseline eGFR.Multivariate analysis revealed that UA/Cr was an independent risk factor for renal disease progress(hazard ratio 1.364 [95%CI 1.131-1.646],P = 0.001)independently of age、sex、and other potential confounders.Conclusions: UA/Cr might be a novel predictor of chronic kidney disease progression in T2 DM patients.Background:Uric acid serves as a direct causative factor of renal tubular epithelial cell injury and is highly associated with the progression of chronic kidney disease(CKD).Uric acid is thought to be an independent risk of kidney failure and death of patients with CKD.Lowering serum uric acid therapy can attenuate the progression of CKD.Inflammasomes are intracellular multiprotein complexes that can be activated by many factors and signals.NLRP3 inflammasome is formed after the oligomerization of NLRP3 and subsequent recruitment of adaptor ASC(apoptosisassociated Speck-like protein with a caspase-recruitment domain)and pro-caspase-1.Many evidences indicate that the NLRP3 inflammasome is associated with the progression of chronic kidney diseases,including diabetic nephropathy and primary chronic glomerulonephritis.In the present study we investigated the effects of uric acid on activity of NLRP3 inflammasome signaling pathways in vitro,In addition,we further explored the mechanism involved in the uric acid-induced NLRP3 inflammasome activation.Method:Tubular epithelial cells were cultured with different concentration of Uric acid(0、200、400、600、800、1000μg/ml).Cell viability was tested by CCK-8 assay and confirmed by Calcein-AM/PI double fluorescence staining.Mitochondrial membrane potential was examined,and the expression of apoptosis-related protein PARP,Bax was also detected by Western Blot.Furthermore,the expression levels of pErk,NLRP3 were also was detected by western blotting,then knew the time of NLRP3 and ERK1/2 actin.Results and Conclusion: The activity of tubular epithelial cells and mitochondrial membrane potential was declined as treated with increased concentrations of uric acid.The expression of ROS,ERK1/2 and NLRP3 were also up-regulated by uric acid in tubular epithelial cells stimulated by uric acid.These findings indicate that ROS/ERK1/2/NLRP3 inflammasome signaling pathway might plays important role in the injury of tubular epithelial cells induced by uric acid.