1] Department of Pathology, University of Washington, Seattle, WA, USA [2] Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY, USA.
Department of Pathology, University of Washington, Seattle, WA, USA.
Lab Invest. 2014 Aug;94(8):851-62. doi: 10.1038/labinvest.2014.80. Epub 2014 Jun 23.
Piperidine-based peroxisome proliferator-activated receptor-α 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 Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic 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 PGF(2α) 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 PGF(2α), 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.
基于哌啶的过氧化物酶体增殖物激活受体-α激动剂是一类有效的药物，可改善糖尿病和肥胖患者的脂质、血糖和炎症指标。本研究旨在确定新型过氧化物酶体增殖物激活受体-α激动剂 CP-900691((S)-3-[3-(1-羧基-1-甲基-乙氧基)-苯基]-哌啶-1-羧酸 4-三氟甲基苄酯; CP)是否可以通过降低血浆甘油三酯来预防 2 型糖尿病的 Black and Tan、Brachyuric (BTBR) ob/ob 小鼠模型的糖尿病肾病。4 周龄雌性 BTBR WT 和 BTBR ob/ob 小鼠接受普通饲料或含 CP(3mg/kg/天)的饲料 14 周。CP 可升高 BTBR WT 小鼠的血浆高密度脂蛋白、白蛋白尿和非酶代谢产物 8-epi PGF(2α)的尿排泄，8-epi PGF(2α)是花生四烯酸的非酶代谢产物，其产量在氧化应激时升高。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、体重和血浆白细胞介素-6，同时改善胰岛素抵抗。尽管 CP 具有这些有益的代谢作用，但对升高的血浆胰岛素、8-epi PGF(2α)排泄和白蛋白尿没有影响，令人惊讶的是，CP 也没有改善糖尿病肾病的发生，对肾脏巨噬细胞的积累、肾小球肥大和系膜基质扩张没有影响。此外，CP 并没有增加 BTBR ob/ob 小鼠的血浆高密度脂蛋白，反而增加了总胆固醇水平。这些发现表明，8-epi PGF(2α)可能与高胰岛素血症、炎症和功能失调的脂蛋白一起，是糖尿病肾病发生的重要因素，应该被视为糖尿病肾病治疗的潜在靶点。
