Peroxisome proliferator-activated receptor α/γ dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice
Peroxisome proliferator-activated receptor α/γ dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice
复制标题
DOI：
10.2337/db06-1134
复制
发表时间：
2007-08-01
期刊：
影响因子：
7.7
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
--
作者：
Cha, Dae Ryong;Zhang, Xiaoyan;Guan, Youfei
过氧化物酶体增殖物激活受体（PPARs）是核转录因子，在胰岛素敏感性、脂质代谢和炎症中发挥核心作用。PPAR α和- γ都在肾脏中表达，它们的激动剂在2型糖尿病中表现出肾脏保护作用。在本研究中，我们研究了PPAR α / γ双激动剂替格列他对2型糖尿病db/db小鼠糖尿病肾病的影响。替格列他治疗db/db小鼠3个月可显著降低空腹血糖和胰岛素抵抗水平的稳态模型评估，但对体重、肥胖或心功能几乎没有影响。替格列他治疗与血浆胰岛素和总甘油三酯水平降低以及血浆脂联素水平升高相关。值得注意的是，替格列azar显著减轻db/db小鼠蛋白尿，显著降低肾小球纤维化、胶原沉积和肾组织中转化生长因子- β 1的表达。在培养的系膜细胞和近端小管细胞中，PPAR α和- γ均有表达，替格列沙治疗消除了高糖诱导的总胶原蛋白产生和I型和IV型胶原基因表达。总的来说，替格列他治疗不仅改善了db/db小鼠的胰岛素抵抗、血糖控制和血脂，而且显著减轻了蛋白尿和肾小球纤维化。这些发现支持双PPAR α / γ激动剂治疗2型糖尿病和糖尿病肾病的效用。
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPAR alpha and -gamma are expressed in the kidney, and their agonists exhibit renoprotective effects in type 2 diabetes. In the present studies, we investigated the effect of the PPAR alpha/gamma dual agonist tesaglitazar on diabetic nephropathy in type 2 diabetic db/db mice. Treatment of db/db mice with tesaglitazar for 3 months significantly lowered fasting plasma glucose and homeostasis model assessment of insulin resistance levels but had little effect on body weight, adiposity, or cardiac function. Treatment with tesaglitazar was associated with reduced plasma insulin and total triglyceride levels and increased plasma adiponectin levels. Notably, tesaglitazar markedly attenuated albuminuria and significantly lowered glomerulofibrosis, collagen deposition, and transforming growth factor-beta 1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPAR alpha and -gamma were expressed, tesaglitazar treatment abolished high glucose- induced total collagen protein production and type I and IV collagen gene expression. Collectively, tesaglitazar treat ment not only improved insulin resistance, glycemic control, and lipid profile but also markedly attenuated albuminuria and renal glomerular fibrosis in db/db mice. These findings support the utility of dual PPAR alpha/gamma agonists in treating type 2 diabetes and diabetic nephropathy.