Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model
Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model
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DOI：
10.1093/ndt/gfm715
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发表时间：
2008-04-01
影响因子：
6.1
通讯作者：
Miyata, Toshio
中科院分区：
文献类型：
--
作者：
Ohtomo, Shuichi;Nangaku, Masaomi;Miyata, Toshio
背景慢性肾缺氧被认为是糖尿病肾病（DN）的发病机制之一。钴增强缺氧诱导因子（HIF）的活性，这是防御缺氧的关键因子。评价其对DN的长期疗效。给高血压、2型糖尿病肾病大鼠（SHRNDmcr-cp）注射氯化钴。治疗开始于13周龄，持续26周。钴不能纠正高血压和代谢异常（肥胖、高血脂和高胆固醇血症），但能减少蛋白尿和组织学肾损伤。钴上调肾脏HIF-1 α和HIF-2 α表达，并增加HIF调节基因的表达，包括促红细胞生成素、血管内皮生长因子和血红素加氧酶-1。钴显著降低了肾脏转化生长因子（TGF）-β和结缔组织生长因子（CTGF）的表达。钴还显著降低了氧化应激标志物NADPH氧化酶的肾脏表达和晚期糖基化标志物戊糖苷的肾脏含量。钴实现了独立于代谢状态和血压的肾脏保护。其作用归因于HIF和HIF调节基因的上调以及减轻晚期糖基化和氧化应激。
Background. Chronic renal hypoxia is suspected to play a pathogenic role in the genesis of diabetic nephropathy (DN). Cobalt enhances the activity of the hypoxia-inducible factor (HIF), a key factor in the defence against hypoxia. Its long-term effect on DN is evaluated.Methods. Cobalt chloride was given to hypertensive, type 2 diabetic rats with nephropathy (SHRNDmcr-cp). Treatment was initiated at the age of 13 weeks and continued for 26 weeks.Results. Cobalt did not correct hypertension and metabolic abnormalities (obesity, hyperglycaemia and hyperlipidaemia) but reduced proteinuria as well as histological kidney injury. Cobalt upregulated renal HIF-1alpha and HIF-2alpha expression and increased the expression of HIF-regulated genes, including erythropoietin, vascular endothelial growth factor and heme oxygenase-1. The renal expression of transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) was significantly reduced by cobalt. The renal expression of NADPH oxidase, a marker of oxidative stress, and the renal content of pentosidine, a marker of advanced glycation, were also significantly reduced by cobalt.Conclusions. Cobalt achieved renal protection independently of metabolic status and blood pressure. Its effect was attributed to the upregulation of HIF and HIF-regulated genes and to a mitigated advanced glycation and oxidative stress.