Effects of CP-900691, a novel peroxisome proliferator-activated receptor α, agonist on diabetic nephropathy in the BTBR ob/ob mouse.
Effects of CP-900691, a novel peroxisome proliferator-activated receptor α, agonist on diabetic nephropathy in the BTBR ob/ob mouse.
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DOI：
10.1038/labinvest.2014.80
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发表时间：
2014-08
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以哌啶为基础的过氧化体增殖物激活受体α激动剂是在改善糖尿病和肥胖症的血脂、血糖和炎症指标方面有效的药物。本研究试图确定这类新型药物中的一员CP-900691((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic酸(4-三氟甲基苯甲酯)(CP)是否可以通过降低血浆甘油三酯来预防2型糖尿病BTBRob/ob小鼠模型的糖尿病肾病。4周龄雌性BTBR WT和BTBR ob/ob小鼠分别给予普通饲料或含CP(3 mg/kg/d)的饲料喂养14周。CP增加了BTBR WT小鼠的血浆高密度脂蛋白、蛋白尿和尿8-epi-PGF2α的排泄，8-epi PGF2是花生四烯酸非酶代谢的产物，其产量在氧化应激时增加。在BTBR ob/ob小鼠中，CP可降低血浆甘油三酯和非酯化脂肪酸、空腹血糖、体重和血浆白介素6，同时改善胰岛素抵抗。尽管有这些有益的代谢作用，CP对血浆胰岛素升高、8-epi-PGF2α排泄和蛋白尿没有影响，令人惊讶的是，CP并没有改善糖尿病肾病的发展，对肾脏巨噬细胞聚集、肾小球肥大和系膜基质扩张增加没有影响。此外，CP并没有增加BTBR ob/ob小鼠的血浆高密度脂蛋白，而反常地增加了总胆固醇水平。这些结果表明，8-epi-PGF2α可能与高胰岛素血症、炎性和功能障碍的脂蛋白一起参与糖尿病肾病的发生发展，应考虑作为治疗糖尿病肾病的潜在靶点。
Piperidine-based peroxisome proliferator-activated receptor alpha agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester) (CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the BTBR ob/ob mouse model of type 2 diabetes mellitus. 4-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg/day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria and urinary excretion of 8-epi PGF2α, a product of the non-enzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF2α excretion and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF2α, possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.
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影响因子：
120.7
作者：
de Boer, Ian H.;Rue, Tessa C.;Hall, Yoshio N.;Heagerty, Patrick J.;Weiss, Noel S.;Himmelfarb, Jonathan
通讯作者：
Himmelfarb, Jonathan
影响因子：
13.6
作者：
Fujita, Hiroki;Fujishima, Hiromi;Takahashi, Takamune
通讯作者：
Takahashi, Takamune
影响因子：
19.6
作者：
Montero, A;Munger, KA;Badr, KF
通讯作者：
Badr, KF
影响因子：
3.9
作者：
Latruffe, N;Vamecq, J
通讯作者：
Vamecq, J
影响因子：
3
作者：
Cao, Changchun;Wan, Xin;Wu, Wenfang
通讯作者：
Wu, Wenfang