Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress.
Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress.
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DOI：
10.1161/hypertensionaha.113.01425
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Palm F
中科院分区：
文献类型：
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作者：
Friederich-Persson M;Thörn E;Hansell P;Nangaku M;Levin M;Palm F
糖尿病肾病与氧化应激增加和肾组织缺氧密切相关。氧化应激增加导致肾脏耗氧量增加，导致肾组织缺氧。迄今为止，还很难确定肾脏缺氧本身对于肾病发展的作用。我们检验了这样的假设：肾脏缺氧，在没有高血糖或氧化应激升高等混杂因素的情况下，会导致肾病。为了诱导肾脏缺氧，连续 30 天给大鼠注射二硝基苯酚（灌胃 30 毫克/天/公斤），这是一种线粒体解偶联剂，会增加耗氧量并导致肾脏缺氧。此后，测定肾小球滤过率、肾血流量、肾耗氧量、肾氧张力、肾葡萄糖和糖原浓度、氧化应激标志物、尿蛋白排泄和组织学，并与媒介物处理的对照进行比较。二硝基苯酚不会影响动脉血压、肾血流量、肾小球滤过率、血糖或氧化应激标志物，但会增加肾脏耗氧量，降低皮质和髓质葡萄糖和糖原的浓度，导致肾内组织缺氧。此外，二硝基苯酚治疗增加了尿蛋白排泄、肾脏波形蛋白表达和炎症细胞浸润。总之，线粒体耗氧量增加会导致肾脏缺氧和随后的肾病。重要的是，这些结果表明，肾组织缺氧本身，在不混淆高血糖或氧化应激的情况下，可能足以引发肾病的发展，因此证明了治疗肾病的新干预靶点。
Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. It has so far been difficult to determine the role of kidney hypoxia per se for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg/day/kg by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion and histology were determined and compared to vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose or markers of oxidative stress, but increased kidney oxygen consumption and reduced cortical and medullary concentrations of glucose and glycogen and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.