title: The dipeptidyl peptidase-4 inhibitor sitagliptin protects against dyslipidemia-related kidney injury in Apolipoprotein E knockout mice.
abstract: 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.
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. lijj6116@163.com.
authors: Jingjing
authors: J
authors: Li
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. mpguan@163.com.
authors: Meiping
authors: M
authors: Guan
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. xichongli@163.com.
authors: Chenzhong
authors: C
authors: Li
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. lv.fu.ping@163.com.
authors: Fuping
authors: F
authors: Lyv
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. emilyzengym@163.com.
authors: Yanmei
authors: Y
authors: Zeng
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. achloe@sina.cn.
authors: Zongji
authors: Z
authors: Zheng
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. weiwei7408@hotmail.com.
authors: Chengzhi
authors: C
authors: Wang
authors: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510150, China. xueyaoming999@126.com.
authors: Yaoming
authors: Y
authors: Xue
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005353:Fibronectins; D011719:Pyrazines; D053773:Transforming Growth Factor beta1; D014230:Triazoles; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D000068900:Sitagliptin Phosphate