Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition or dietary AGE control in diabetic nephropathy
huangtingliubin 添加于 2009-12-19 13:47
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作 者
Tan AL, Sourris KC, Harcourt BE, Thallas-Bonke V, Penfold S, Andrikopoulos S P, Thomas MC, O'Brien RC, Bierhaus A, Cooper ME, Forbes JM, Coughlan MT 摘 要
Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) generate ROS and therefore this study evaluated the effects of RAGE-deletion, decreasing AGE accumulation or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE(-/-)) mice were fed high or low AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride and followed for 24 weeks. Diabetic RAGE(-/-) mice were protected against albuminuria, hyperfiltration, glomerulosclerosis, decreased renal mitochondrial ATP production and excess generation of both mitochondrial and cytosolic superoxide. While glomerulosclerosis, tubulointerstitial expansion and hyperfiltration were improved in diabetic mice treated with alagebrium, there was no effect on urinary albumin excretion. Both diabetic RAGE(-/-) and alagebrium treated mice had an attenuation of renal RAGE expression and decreased renal and urinary AGE (CML) levels. Low AGE diets did not confer renoprotection, lower the AGE burden or renal RAGE expression nor improve cytosolic or mitochondrial superoxide generation. Renal uncoupling protein-2 gene expression and mitochondrial membrane potential were attenuated by all therapeutic interventions in diabetic mice. In the present study, diverse approaches to block the AGE-RAGE axis have disparate effects on DN, which has potential clinical implications for the way this axis should be targeted in man. Key words: diabetic nephropathy, oxidative stress, RAGE, advanced glycation.-
详细资料
- 文献种类:期刊
- 期刊名称: American Journal of Physiology. Renal Physiology
- 期刊缩写: Am J Physiol Renal Physiol
- 期卷页: 2009年
- 地址: Baker IDI Heart and Diabetes Institute
- ISBN: 1522-1466
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