Li Jingjing, Guan Meiping, Li Chenzhong, Lyv Fuping, Zeng Yanmei, Zheng Zongji, Wang Chengzhi, Xue Yaoming
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China.
Int J Mol Sci. 2014 Jun 26;15(7):11416-34. doi: 10.3390/ijms150711416.
The goal of this study was to investigate the possible protective effects of sitagliptin against dyslipidemia-related kidney injury in apolipoprotein E knockout (apoE-/-) mice. Eight-week-old male apoE-/- mice were randomized to receive either a high fat diet (HFD, apoE-/- group) or HFD mixed with sitagliptin (sita + apoE-/- group) for 16 weeks. A control group of age- and gender-matched C57BL/6J mice were fed a HFD. The apoE-/- group exhibited increases in body weight and serum lipid levels in addition to high-density lipoprotein, and increases in 24-h urinary 8-hydroxy-2-deoxyguanosine and albuminuria excretion. Decreased insulin sensitivity was also observed in the apoE-/- group. These mice additionally contained enlargements of the glomerular mesangial matrix area, lipid deposition area, and renal interstitium collagen area. The apoE-/- group also demonstrated down-regulation of phosphorylated AMP-activated protein kinase (AMPK), increases in renal mRNA expression of transforming growth factor-beta 1 (TGF-β1) and fibronectin (FN), and increased protein expression of Akt, TGF-β1, FN and p38/ERK mitogen-activated protein kinase (MAPK). Sitagliptin treatment successfully ameliorated all the deleterious effects of dyslipidemia tested. To our knowledge, this is the first time that sitagliptin has been shown to reverse the renal dysfunction and structural damage induced by dyslipidemia in apoE-/- mice. Our results suggest that the renoprotective mechanism of sitagliptin may be due to a reduction in Akt levels, a restoration of AMPK activity, and inhibition of TGF-β1, FN, and p38/ERK MAPK signaling pathways.
本研究的目的是探讨西他列汀对载脂蛋白E基因敲除（apoE-/-）小鼠血脂异常相关肾损伤的潜在保护作用。将8周龄雄性apoE-/-小鼠随机分为两组，一组给予高脂饮食（HFD，apoE-/-组），另一组给予高脂饮食混合西他列汀（西他列汀+apoE-/-组），持续16周。选取年龄和性别匹配的C57BL/6J小鼠作为对照组，给予高脂饮食。apoE-/-组除高密度脂蛋白外，体重和血脂水平升高，24小时尿8-羟基-2-脱氧鸟苷和蛋白尿排泄增加。apoE-/-组还观察到胰岛素敏感性降低。这些小鼠的肾小球系膜基质面积、脂质沉积面积和肾间质胶原面积也增大。apoE-/-组还表现出磷酸化AMP活化蛋白激酶（AMPK）下调，肾组织中转化生长因子-β1（TGF-β1）和纤连蛋白（FN）的mRNA表达增加，Akt、TGF-β1、FN和p38/ERK丝裂原活化蛋白激酶（MAPK）的蛋白表达增加。西他列汀治疗成功改善了所检测的血脂异常的所有有害影响。据我们所知，这是首次表明西他列汀可逆转apoE-/-小鼠血脂异常所致的肾功能障碍和结构损伤。我们的结果表明，西他列汀的肾脏保护机制可能是由于Akt水平降低、AMPK活性恢复以及对TGF-β1、FN和p38/ERK MAPK信号通路的抑制。
