Objective:Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE).This study aimed to assess the effect of ato...Objective:Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE).This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney.Methods:Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks).Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods.Renal AGEs,RAGE,endogenous secretory RAGE (esRAGE),and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.Results:Mesangial expansion and microalbuminuria were aggravated in diabetic rats,and improved with atorvastatin treatment.Serum sRAGE levels were lower in diabetic than in normal rats.After atorvastatin treatment,serum and renal sRAGE levels were up-regulated,while renal RAGE expression was decreased in diabetic rats,associated with a reduction in accumulation of AGEs,though renal esRAGE mRNA expression was not significantly increased.Conclusions:Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation,down-regulating RAGE expression and up-regulating sRAGE in the kidney.展开更多
Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms un...Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.展开更多
文摘Objective:Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE).This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney.Methods:Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks).Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods.Renal AGEs,RAGE,endogenous secretory RAGE (esRAGE),and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.Results:Mesangial expansion and microalbuminuria were aggravated in diabetic rats,and improved with atorvastatin treatment.Serum sRAGE levels were lower in diabetic than in normal rats.After atorvastatin treatment,serum and renal sRAGE levels were up-regulated,while renal RAGE expression was decreased in diabetic rats,associated with a reduction in accumulation of AGEs,though renal esRAGE mRNA expression was not significantly increased.Conclusions:Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation,down-regulating RAGE expression and up-regulating sRAGE in the kidney.
文摘Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.
