Attenuation of Kidney Injuries Maintains Serum Sulfatide Levels Dependent on Hepatic Synthetic Ability: A Possible Involvement of Oxidative Stress
Attenuation of Kidney Injuries Maintains Serum Sulfatide Levels Dependent on Hepatic Synthetic Ability: A Possible Involvement of Oxidative Stress
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DOI：
10.1620/tjem.227.1
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发表时间：
2012-05-01
影响因子：
2.2
通讯作者：
Hara, Atsushi
中科院分区：
文献类型：
--
作者：
Sheng, Xiaona;Nakajima, Takero;Hara, Atsushi
血清硫脂是脂蛋白中主要的鞘糖脂。虽然血清硫脂主要由肝脏合成和分泌，但当肾脏受损时，它们会显著降低。我们最近的实验研究使用小鼠蛋白质超载肾病模型提出了一个假设的机制，即血清硫脂减少，由于肾功能不全。这是一种硫苷脂合成酶--糖苷磺基转移酶（CST）的肝脏表达降低的结果，该酶与氧化应激的全身性增强相关。然而，有一种可能性，即实验过程，蛋白质超载本身，直接影响了硫苷脂代谢和氧化应激在肝脏中。为了确定肾功能不全是否真的通过氧化应激减少了肝脏硫苷脂的合成，我们检测了硫苷脂水平，代谢硫苷脂酶的肝脏含量，以及使用氯贝丁酯（一种代表性的降血脂药物）进行肾保护治疗的蛋白质超载小鼠的氧化应激程度。蛋白超负荷小鼠肾组织损伤明显，肝脏氧化应激增强，血清和肝脏硫代脂肪酸水平降低，肝脏CST表达减少。氯贝丁酯治疗减弱了小鼠的肾损伤和肝氧化应激，同时维持了血清/肝硫苷脂水平和肝CST含量。由于没有蛋白超载治疗的氯贝特单药治疗对这些肝脏参数的影响最小，因此肝硫苷脂的合成似乎受到肾功能障碍和随后的氧化应激的强烈影响。这项研究表明，肾功能不全和肝硫脂代谢之间的串扰是由氧化应激介导的。这些结果有助于理解终末期肾病患者的这种现象。
Serum sulfatides are the major glycosphingolipids in lipoproteins. Although serum sulfatides are mainly synthesized and secreted by the liver, they are significantly decreased when the kidneys are impaired. Our recent experimental study using a murine protein-overload nephropathy model suggested a hypothetical mechanism whereby serum sulfatides were reduced due to kidney dysfunction. This was the result of decreased hepatic expression of a sulfatide synthetic enzyme, cerebroside sulfotransferase (CST), which is associated with systemic enhancement of oxidative stress. However, there is a possibility that the experimental process, protein-overload itself, directly affected the sulfatide metabolism and oxidative stress in the liver. To determine whether kidney dysfunction actually reduces the hepatic synthesis of sulfatides via oxidative stress, we examined sulfatide levels, the hepatic content of metabolic sulfatide enzymes, and the degree of oxidative stress in protein-overload mice subjected to renoprotective therapy using clofibrate, a representative hypolipidemic medicine. Protein-overload mice exhibited marked kidney injuries, enhancement of hepatic oxidative stress, decreased levels of serum and hepatic sulfatides, and decreased expression of hepatic CST. The clofibrate treatment attenuated kidney damage and hepatic oxidative stress while maintaining serum/hepatic sulfatide levels and hepatic CST content in the mice. Because clofibrate monotherapy without protein-overload treatment only minimally affected these hepatic parameters, the hepatic synthesis of sulfatides appeared to be strongly influenced by kidney dysfunction and subsequent oxidative stress. This study suggests that the crosstalk between kidney dysfunction and hepatic sulfatide metabolism is mediated by oxidative stress. These results should help to understand the phenomenon in patients with end-stage kidney disease.