Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia
Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia
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DOI：
10.1681/asn.2004080674
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发表时间：
2005-04-01
影响因子：
13.6
通讯作者：
Lerman, LO
中科院分区：
文献类型：
--
作者：
Chade, AR;Herrmann, J;Lerman, LO
高胆固醇血症（HC）和动脉粥样硬化常伴随并加重肾脏疾病。蛋白酶体抑制剂（PSI）可能通过减少促炎的核因子 - κB的激活来降低增殖和炎症。然而，在高胆固醇血症肾脏中从未证实过慢性蛋白酶体抑制作用。四组猪（每组n = 7）在接受12周正常（N）饮食或2%高胆固醇饮食，或者在正常饮食和高胆固醇饮食基础上补充（N + PSI和HC + PSI）MLN - 273（每周皮下注射两次，每次0.08 mg/kg）后进行研究。在基线时以及使用乙酰胆碱进行血管舒张激发后，利用电子束计算机断层扫描在体内对肾血流动力学和功能进行量化。使用免疫印迹、聚合酶链反应和免疫组织化学在体外对肾组织进行研究。血清胆固醇在HC组和HC + PSI组中升高程度相似。各组之间基础肾血流量相似，而N + PSI组和HC + PSI组的肾小球滤过率均降低。HC组中对乙酰胆碱的肾血管和功能反应减弱，在HC + PSI组中恢复正常（表明肾内皮功能改善），同时伴有肾内皮素、核因子 - κB降低以及内皮型一氧化氮合酶表达增加。同时，HC + PSI组动物还显示出NAD(P)H氧化酶表达升高和循环氧化型低密度脂蛋白升高，提示可能存在氧化应激增加。这项研究表明，在高胆固醇血症中慢性PSI干预可改善肾内皮对刺激的功能反应，可能是通过调节一氧化氮的可利用性和内皮素实现的。此外，PSI可能通过调节核因子 - κB通路减少肾内炎症，但可能潜在地增加氧化应激，这需要进一步研究。这项研究可能支持泛素/蛋白酶体系统在高胆固醇血症和早期动脉粥样硬化肾脏中的作用。
Hypercholesterolemia (HC) and atherosclerosis often accompany and aggravate renal disease. Proteasome inhibitors (PSI) can decrease proliferation and inflammation, likely by reducing activation of the proinflammatory NF-kappa B. However, chronic proteasome inhibition has never been demonstrated in the HC kidney. Four groups of pigs (n = 7 each) were studied after a 12-wk normal (N) or 2% HC diet alone or supplemented (N+PSI and HC+PSI) with MLN-273 (0.08 mg/kg subcutaneously twice weekly). Renal hemodynamics and function were quantified in vivo using electron-beam computed tomography at baseline and after vasodilator challenge using acetylcholine. Renal tissue was studied ex vivo using immunoblotting, PCR, and immunohistochemistry. Serum cholesterol was similarly elevated in HC and HC+PSI. Basal renal blood flow was similar among the groups, whereas GFR was decreased in both N+PSI and HC+PSI. The blunted renovascular and functional responses to acetylcholine in HC were normalized in HC+PSI (suggesting renal endothelial function improvement), which was accompanied by decreased renal endothelin, NF-kappa B, and augmented endothelial nitric oxide synthase expression. In parallel, HC+PSI animals also showed elevated NAD(P)H oxidase expression and circulating oxidized LDL, suggesting a potential for increased oxidative stress. This study shows that chronic PSI intervention in HC improves renal endothelial functional responses to challenge, possibly by modulating nitric oxide availability and endothelin. Furthermore, PSI may decrease intrarenal inflammation through modulation of the NF-kappa B pathway but may potentially increase oxidative stress, which warrants further investigation. This study may support a role for the ubiquitin/proteasome system in the kidney in HC and early atherosclerosis.