Effects of 4-phenylbutyric acid on the process and development of diabetic nephropathy induced in rats by streptozotocin: Regulation of endoplasmic reticulum stress-oxidative activation
Effects of 4-phenylbutyric acid on the process and development of diabetic nephropathy induced in rats by streptozotocin: Regulation of endoplasmic reticulum stress-oxidative activation
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DOI：
10.1016/j.taap.2010.04.005
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Yuan, Fa-Huan
中科院分区：
文献类型：
--
作者：
Luo, Zhi-Feng;Feng, Bing;Yuan, Fa-Huan
氧化应激可能参与了糖尿病肾病（DN）的发病机制，但确切的调控机制尚不清楚。最近的研究表明，化学分子伴侣4-苯基丁酸（4-PBA）可以通过减轻内质网（ER）应激来抑制氧化应激。因此，我们假设4-PBA可以通过抑制氧化应激在DN大鼠提供肾脏保护。雄性SD大鼠随机分为正常对照组（NC）、链脲佐菌素（STZ）诱导的DN模型组和DN +4-PBA（1 g/kg）治疗组。在第4、8和12周结束时，检测羟脯氨酸含量、NADPH氧化酶活性和磷酸化肌醇需要酶-1 α的表达。检测各组大鼠肾脏组织中p-IRE 1 α、p47 phox、硝基酪氨酸（NT）和NF-E2相关因子2（Nrf 2）的含量，并检测血清和尿液中丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性;在12周结束时检测所有大鼠的肾核因子-κ B（NF-κ B）活性。与正常对照组相比，DN组大鼠肾脏羟脯氨酸含量、NADPH氧化酶活性明显升高。肾组织NF-κ B B活性、p-IRE 1 α、p47 phox、NT和Nrf 2表达，DN大鼠血清和尿液中MDA水平明显高于NC大鼠，SOD活性明显低于NC大鼠。这些变化被抑制4-PBA的管理。这些发现首次证明，4-PBA治疗通过调节ER应激-氧化激活显著抑制大鼠糖尿病肾病的过程和发展。(C)2010年爱思唯尔公司All rights reserved.
Oxidative stress may contribute to the pathogenesis of diabetic nephropathy (DN), although the precise regulatory mechanism is still unclear. Recent reports have shown that chemical molecular chaperone 4-phenylbutyric acid (4-PBA) can suppress oxidative stress by attenuating endoplasmic reticulum (ER) stress. We therefore hypothesized that 4-PBA could provide renoprotection through the suppression of oxidative stress in DN rats. Male Sprague-Dawley (SD) rats were randomly divided into three groups: a normal control (NC) group, a streptozotocin (STZ)-induced DN model group, and a DN plus 4-PBA (1 g/kg) treatment group. At the end of 4, 8, and 12 weeks, hydroxyproline content, NADPH oxidase activity and the expression of phosphorylation of inositol-requiring enzyme-1 alpha (p-IRE1 alpha), p47phox, nitrotyrosine (NT) and NF-E2-related factor 2 (Nrf2) in the kidneys of all rats were determined; malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity in serum and urine were also detected; renal nuclear factor kappa B (NF-kappa B) activity in all of the rats was examined at the end of 12 weeks. Compared with the NC group, the DN rats showed a significant increase in hydroxyproline content, NADPH oxidase activity. NF-kappa B activity, the expression of p-IRE1 alpha, p47phox, NT and Nrf2 in renal tissue; markedly, MDA levels were higher and SOD activity was lower in serum and urine of DN rats than in NC rats for the indicated time. These alterations were inhibited by the administration of 4-PBA. These findings first demonstrated that treatment with 4-PBA significantly inhibits the process and development of diabetic nephropathy in rats through the regulation of ER stress-oxidative activation. (C) 2010 Elsevier Inc. All rights reserved.