Albumin overload activates intrarenal renin-angiotensin system through protein kinase C and NADPH oxidase-dependent pathway
Albumin overload activates intrarenal renin-angiotensin system through protein kinase C and NADPH oxidase-dependent pathway
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DOI：
10.1097/hjh.0b013e32834786f0
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发表时间：
2011-07-01
影响因子：
4.9
通讯作者：
Hou, Fan F.
中科院分区：
文献类型：
--
作者：
Cao, Wei;Zhou, Qiu G.;Hou, Fan F.
目的肾内肾素-血管紧张素系统（RAS）的不适当激活在高血压和肾损害的发病机制中起重要作用。然而，根本的机制仍然难以捉摸。蛋白尿已被证明可引起肾RAS激活。本研究进行测试白蛋白触发激活的RAS.Design和方法NRK 52 E细胞，大鼠肾近端肾小管细胞系，参与细胞内信号通路与白蛋白水平增加孵育。雌性Wistar-Kyoto大鼠行单侧肾切除术后，每天腹腔注射不同剂量的牛血清白蛋白（BSA），建立蛋白质超载大鼠模型（0.5、1.0和5.0 g/kg）或与夹竹桃麻素胃内给药的组合结果高浓度白蛋白通过内吞受体megalin和cubilin激活RAS。高水平白蛋白通过蛋白激酶C（PKC）-NADPH氧化酶依赖性途径触发细胞内活性氧的产生，进而导致核因子-κ B（NF-κ B）和活化蛋白-1（AP-1）活化。抑制PKC或NADPH氧化酶可消除白蛋白诱导的RAS激活。在蛋白质超载大鼠模型中，肾近端小管细胞中RAS的活化显著增加，与PKC、NADPH氧化酶、NF-κ B和AP-1的活化一致。夹竹桃素对NADPH氧化酶的慢性抑制可显著改善肾内RAS的激活。结论高浓度白蛋白暴露于肾小管上皮细胞可通过PKC-NADPH氧化酶依赖性途径激活RAS。J Hypertens 29：1411-1421（C）2011年威科健康垂直酒吧Lippincott威廉姆斯&威尔金斯。
Objective Inappropriate activation of the intrarenal renin-angiotensin system (RAS) plays an important role in the pathogenesis of hypertension and renal injury. However, the underlying mechanisms remain elusive. Proteinuria has been shown to elicit the renal activation of RAS. The present study was performed to test the intracellular signal pathway involved in albumin-triggered activation of RAS.Design and methods NRK52E cells, a rat renal proximal tubular cell line, were incubated with increased levels of albumin. The rat model of protein overload was established in female Wistar-Kyoto rats that were subjected to unilateral nephrectomy followed by daily intraperitoneal injection of BSA at various doses (0.5, 1.0, and 5.0 g/kg) or combination with intragastric administration of apocynin ( 100 mg/kg per day), an inhibitor of NADPH oxidase.Results Exposure of the cells to high levels of albumin activated the RAS through the endocytic receptors megalin and cubilin. High levels of albumin triggered the production of intracellular reactive oxygen species by a protein kinase C (PKC)-NADPH oxidase- dependent pathway and this, in turn, led to activation of nuclear factor-kappa B (NF-kappa B) and activation protein-1 (AP-1). Inhibition of PKC or NADPH oxidase abolished albumin-induced activation of RAS. In a protein overload rat model, activation of RAS in renal proximal tubular cells was significantly increased, coincident with activation of PKC, NADPH oxidase, NF-kappa B, and AP-1. Chronic inhibition of NADPH oxidase by apocynin largely ameliorated intrarenal activation of RAS.Conclusion Exposure of renal tubular epithelial cells with high levels of albumin triggers activation of RAS via a PKC-NADPH oxidase- dependent pathway. J Hypertens 29: 1411-1421 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.