The breakdown of pre-existing advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes
The breakdown of pre-existing advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes
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DOI：
10.1096/fj.02-1102fje
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发表时间：
2003-07-01
期刊：
影响因子：
4.8
通讯作者：
Cooper, ME
中科院分区：
文献类型：
--
作者：
Forbes, JM;Thallas, V;Cooper, ME
晚期糖基化终末产物(AGEs)的肾脏积聚与糖尿病肾病的进展有关。用交联剂如ALT-711裂解肾脏内预先形成的AGEs，可能会对糖尿病患者产生肾保护作用。STZ糖尿病大鼠被随机分为a)不治疗(D)；b)使用AGE交联剂ALT-711，第16-32周(DALT早期)；c)ALT-711，第24-32周(DALT晚期)。用ALT-711治疗后，糖尿病患者血清和肾脏AGE多肽荧光显著降低，肾脏羧甲基赖氨酸和RAGE免疫染色减少。糖尿病组尾部肌腱胶原的交联性仅通过16周的ALT-711治疗而减弱。ALT-711，与疗程、延缓的白蛋白排泄率(AER)、血压降低和肾脏肥大无关。它还可降低糖尿病引起的转化生长因子β1、结缔组织生长因子和IV型胶原基因表达的增加。但肾小球硬化指数、肾小管间质面积、肾组织总胶原、硝基酪氨酸、IV型胶原蛋白表达和转化生长因子β1仅在早期ALT治疗时才有改善。这项研究证明了交联剂作为治疗糖尿病肾病的有效性，并描述了不仅对肾脏年龄的影响，而且对肾脏损伤的假定介质，如促硬化性细胞因子和氧化应激的影响。
Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre-formed AGEs within the kidney by a cross-link breaker, such as ALT-711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross-link breaker, ALT-711, weeks 16-32 (DALT early); and c) ALT-711, weeks 24-32 (DALT late). Treatment with ALT-711 resulted in a significant reduction in diabetes-induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllsine and RAGE immunostaining. Cross-linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT-711 treatment. ALT-711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes-induced increases in gene expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotryrosine, protein expression of collagen IV, and TGF-beta1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.