Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor α
Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor α
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DOI：
10.2337/diabetes.55.04.06.db05-1329
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发表时间：
2006-04-01
期刊：
影响因子：
7.7
通讯作者：
Breyer, MD
中科院分区：
文献类型：
--
作者：
Park, CW;Kim, HW;Breyer, MD
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPAR）α是配体激活核受体超家族的成员，在脂质代谢和葡萄糖稳态中起重要作用，在肾脏中高度表达。本研究的目的是利用PPAR α基因敲除小鼠和培养的小鼠系膜细胞来确定PPAR α在糖尿病肾病发病机制中的作用。使用低剂量链脲佐菌素方案在8周龄雄性129 SvJ PPAR α敲除小鼠和野生型小鼠中诱导糖尿病。糖尿病PPARa基因敲除小鼠和野生型小鼠出现空腹血糖（P < 0.001）和HbA（1c）水平升高（P < 0.001）。在高血糖16周后，对糖尿病和非糖尿病的PPAR α基因敲除小鼠和野生型小鼠的肾功能和组织病理学变化进行了评价。糖尿病野生型小鼠皮质小管的过氧化物酶体增殖物激活受体α免疫染色因高血糖而升高。在糖尿病PPAR α基因敲除小鼠中，伴有蛋白尿、肾小球硬化和系膜区扩张的肾脏疾病比糖尿病野生型小鼠更严重（P < 0.05），并伴有血清游离脂肪酸和甘油三酯水平升高（P < 0.01）。此外，他们表现出增加的IV型胶原和骨桥蛋白，这是与增加巨噬细胞浸润和肾小球凋亡的肾免疫染色。非糖尿病PPAR α基因敲除小鼠和野生型小鼠与糖尿病PPAR α野生型小鼠之间的肾脏疾病指标无显著差异。体外研究表明，高葡萄糖水平显着增加IV型胶原蛋白的表达，转化生长因子β 1，白细胞粘附到培养的系膜细胞的数量。白细胞的粘附被PPARa激动剂非诺贝特抑制。总之，PPAR α缺乏似乎通过细胞外基质形成、炎症和循环游离脂肪酸和甘油三酯浓度的增加而加重糖尿病肾病的严重程度。PPAR α激动剂可作为1型糖尿病肾病的有用治疗剂。
Peroxisome proliferator-activated receptor (PPAR)alpha, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies we-re aimed at determining the role of PPAR(x in the pathogenesis of diabetic nephropathy using PPAR alpha-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPAR alpha-knockout and wild-type mice. Diabetic PPARa-knockout and wildtype mice developed elevated fasting blood glucose (P < 0.001) and HbA(1c) levels (P < 0.001). Renal functional and histopathological changes in diabetic and nondiabetic PPAR alpha-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPAR alpha immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPAR alpha-knockout mice, renal disease with accompanying albuminuria, glomerular sclerosis, and mesangial area expansion was more severe than in diabetic wild-type mice (P < 0.05) and was accompanied by increased levels of serum free fatty acids and triglycerides (P < 0.01). Furthermore, they exhibited increased renal immunostaining for type IV collagen and osteopontin, which was associated with increased macrophage infiltration and glomerular apoptosis. There were no significant differences in these indexes of renal disease between nondiabetic PPAR alpha-knockout and wild-type mice and diabetic PPAR alpha wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-beta 1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPARa agonist fenofibrate. Taken together, PPAR alpha deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. PPAR alpha agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy.