Intrarenal metabolomics reveals the association of local organic toxins with the progression of diabetic kidney disease.
Intrarenal metabolomics reveals the association of local organic toxins with the progression of diabetic kidney disease.
复制标题
DOI：
10.1016/j.jpba.2011.11.010
复制
发表时间：
2012-02
影响因子：
3.4
通讯作者：
Tie Zhao;Haojun Zhang;Tingting Zhao;Xianglin Zhang;Jin-Jin Lu-Jin;Tingting Yin;Qiong-lin Liang;Yi-ming Wang;G. Luo;Huiyao Lan;Ping Li
中科院分区：
文献类型：
--
作者：
Tie Zhao;Haojun Zhang;Tingting Zhao;Xianglin Zhang;Jin-Jin Lu-Jin;Tingting Yin;Qiong-lin Liang;Yi-ming Wang;G. Luo;Huiyao Lan;Ping Li
糖尿病肾病（DKD）的病理发展可能涉及肾组织的代谢紊乱。本研究旨在检测DKD大鼠肾皮质代谢物的系统性变化，从而探讨DKD发生的相关机制和福辛普利的治疗作用。采用气相色谱/飞行时间质谱（GC-TOF MS）和液相色谱/飞行时间质谱（UPLC-TOF MS）数据采集平台，对链脲佐菌素诱导的糖尿病大鼠肾皮质灌流标本进行代谢组学分析。我们在糖尿病肾脏中鉴定了许多异常代谢物，包括氨基酸、碳水化合物、多元醇、溶血磷脂、葡萄糖醛酸苷和其他未鉴定的代谢物。其中，肾内有机毒素（包括尿毒症毒素、葡萄糖醛酸苷和葡萄糖毒性相关代谢物）的增加与糖尿病肾损伤（包括24小时尿蛋白水平和肾小管间质损伤指数）高度相关。福辛普利治疗显著减轻糖尿病肾损伤，同时阻断这些有机毒素，特别是马尿酸和葡萄糖醛酸的肾内积累。这些结果表明，肾内有机毒素的蓄积可能是DKD发生发展的重要因素，其机制值得进一步研究。
The pathological development of diabetic kidney disease (DKD) might involve metabolic perturbations in kidney tissue. The present study was designed to detect the systematic alterations of renal cortex metabolites thereby exploring the related mechanisms of DKD development and fosinopril treatment. Based on combined gas chromatography/time-of-flight mass spectrometry (GC–TOF MS) and liquid chromatography/time-of-flight mass spectrometry (UPLC–TOF MS) data acquiring platform, we have performed a metabolomic analysis of perfused renal cortex samples from the diabetic rats induced by streptozocin and treated with or without fosinopril, a pharmacological inhibitor of angiotensin II converting enzyme (ACEI). We identified a number of abnormal metabolites in the diabetic kidney, including groups of amino acids, carbohydrates, polyols, lyso-phospholipids, glucuronides and other unidentified metabolites. Of them, an increase in intrarenal organic toxins including uremic toxins, glucuronides and glucotocixity-associated metabolites are highly correlated with diabetic kidney injury including 24h urinary protein levels and tubulointerstitial injury index. Treatment with fosinopril significantly attenuated diabetic kidney injury, and simultaneously blocked the intrarenal accumulation of these organic toxins, especially hippurate and glucuronides. These results indicate that intrarenal accumulation of organic toxins may be significant for the development of DKD and the related mechanisms deserve to be further investigated.