Effects of lovastatin treatment on the metabolic distributions in the Han:SPRD rat model of polycystic kidney disease.
Effects of lovastatin treatment on the metabolic distributions in the Han:SPRD rat model of polycystic kidney disease.
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DOI：
10.1186/1471-2369-14-165
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发表时间：
2013-07-31
期刊：
影响因子：
2.3
通讯作者：
Edelstein CL
中科院分区：
文献类型：
--
作者：
Klawitter J;Zafar I;Klawitter J;Pennington AT;Klepacki J;Gitomer BY;Schrier RW;Christians U;Edelstein CL
我们之前已经证明洛伐他汀可以减少肾囊肿的体积，改善肾功能在Han:SPRD （Cy/+）大鼠ADPKD模型。由于内皮功能障碍和炎症活动在ADPKD患者中很明显，我们研究洛伐他汀是否能减轻Cy/+大鼠的炎症和血管功能障碍，并改善肾细胞能量代谢。从3-8周龄开始，Cy/+和正常同窝对照动物（+/+）分别接受洛伐他汀（4mg /kg/天）或乙醇治疗。高氯酸萃取后的水溶性和脂质肾部分进行1H-NMR分析。采用靶向液相色谱-串联质谱法（LC-MS/MS）评估血浆和肾组织提取物中的内皮功能障碍、氧化应激和炎症标志物。Cy/+大鼠脂肪酸代谢紊乱，促炎脂氧合酶产生的生物活性脂质的合成增加。洛伐他汀降低炎症标志物，特别是13-HODE， 12-HETE和白三烯B4。在Cy/+大鼠中，洛伐他汀降低了升高的同型半胱氨酸和尿囊素血浆水平，并增加了精氨酸，这是已知的积极影响NO的产生。在肾细胞代谢方面，Cy/+大鼠表现出克雷布斯循环活性降低。洛伐他汀治疗增加了克雷布斯循环活性以及糖酵解乳酸的产生，从而改善了囊肾的整体能量状态。如前所述，洛伐他汀能够降低Cy/+大鼠的肾脏重量和囊肿体积密度。囊肿体积的减小伴随着花生四烯酸介导的炎症标志物的减少、NO前体代谢的正常化和肾脏能量细胞代谢的改善。
We previously demonstrated that lovastatin decreases cyst volume and improves kidney function in the Han:SPRD (Cy/+) rat model of ADPKD. Since endothelial dysfunction and inflammatory activity are evident in patients with ADPKD, we investigated whether lovastatin reduces the inflammation and vascular dysfunction and improves kidney cell energy metabolism of Cy/+ rats. Cy/+ and normal littermate control animals (+/+) were treated with either lovastatin (4 mg/kg/day) or vehicle (ethanol) from 3–8 weeks of age. 1H-NMR analysis was performed on water-soluble and lipid kidney fractions following perchloric acid extraction. Targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess endothelial dysfunction, oxidative stress and inflammation markers in plasma and kidney tissue extracts. Cy/+ rats showed perturbations in fatty acid metabolism and increased synthesis of pro-inflammatory lipoxygenases-produced bioactive lipids was observed. Lovastatin decreased inflammatory markers, specifically 13-HODE, 12-HETE and leukotriene B4. In Cy/+ rats, lovastatin reduced the elevated homocysteine and allantoin plasma levels and increased arginine, that is known to positively affect NO production. In terms of kidney cell metabolism, Cy/+ rats showed reduced Krebs cycle activity. Treatment with lovastatin increased the Krebs cycle activity as well as the glycolytical lactate production, thus improving the overall energy state of the cystic kidney. As previously described, lovastatin was able to decrease kidney weight and cyst volume density in Cy/+ rats. The decrease in cyst volume was accompanied by a reduction in arachidonic acid-mediated inflammation markers, the normalization of metabolism of NO precursors and the improvement of kidney energy cell metabolism.
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DOI：
10.1056/nejmoa0706130
发表时间：
2008-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gutiérrez OM;Mannstadt M;Isakova T;Rauh-Hain JA;Tamez H;Shah A;Smith K;Lee H;Thadhani R;Jüppner H;Wolf M
通讯作者：
Wolf M
影响因子：
13.6
作者：
Kielstein, JT;Böger, RH;Fliser, D
通讯作者：
Fliser, D
影响因子：
13.2
作者：
GILE, RD;COWLEY, BD;GRANTHAM, JJ
通讯作者：
GRANTHAM, JJ
影响因子：
19.6
作者：
Cheung, AK;Sarnak, MJ;Levey, AS
通讯作者：
Levey, AS
DOI：
10.1111/j.1475-097x.2010.00943.x
发表时间：
2010-09-01
影响因子：
1.8
作者：
Heffernan, Kevin S.;Patvardhan, Eshan A.;Kuvin, Jeffrey T.
通讯作者：
Kuvin, Jeffrey T.