Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China.
Toxicol Appl Pharmacol. 2010 Jul;246(1-2):49-57. doi: 10.1016/j.taap.2010.04.005. Epub 2010 Apr 24.
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 (1g/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-1alpha (p-IRE1alpha), 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 kappaB (NF-kappaB) 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-kappaB activity, the expression of p-IRE1alpha, 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.
氧化应激可能导致糖尿病肾病（DN）的发病机制，尽管确切的调节机制尚不清楚。最近的报告表明，化学分子伴侣 4-苯丁酸（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来提供肾脏保护作用在 DN 大鼠中。雄性 Sprague-Dawley（SD）大鼠随机分为三组：正常对照组（NC）、链脲佐菌素（STZ）诱导的 DN 模型组和 DN 加 4-PBA（1g/kg）治疗组。在第 4、8 和 12 周末，测定所有大鼠肾脏中羟脯氨酸含量、NADPH 氧化酶活性以及肌醇需求酶 1α（p-IRE1α）、p47phox、硝基酪氨酸（NT）和核因子-2 相关因子 2（Nrf2）的磷酸化表达；还检测了血清和尿液中丙二醛（MDA）水平和超氧化物歧化酶（SOD）活性；所有大鼠在第 12 周末检测了肾核因子 kappaB（NF-kappaB）活性。与 NC 组相比，DN 大鼠肾组织中羟脯氨酸含量、NADPH 氧化酶活性、NF-kappaB 活性、p-IRE1α、p47phox、NT 和 Nrf2 的表达显著增加；明显的是，与 NC 大鼠相比，DN 大鼠血清和尿液中的 MDA 水平升高，SOD 活性降低在指示时间内。4-PBA 的给药抑制了这些改变。这些发现首次表明，通过调节内质网应激-氧化激活，4-PBA 治疗可显著抑制大鼠糖尿病肾病的发生和发展。
