title: Exendin-4 alleviates high glucose-induced rat mesangial cell dysfunction through the AMPK pathway.
abstract: OBJECTIVE
  Glucagon-like peptide-1 (GLP-1), which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate diabetic nephropathy in experimental models. However, the mechanisms through which GLP-1 modulates renal function remained illdefined. The present study investigated the putative mechanisms underlying effects of exendin-4, a GLP-1 analog, on mesangial cell proliferation and fibronectin.
  
  
  METHODS
  Rat mesangial cells (MCs) were treated with exendin-4 under high glucose conditions. AMP-activated protein kinase (AMPK) inhibitors (compound C) and agonists (AICAR) were used to analyze the role of this kinase. Cell proliferation was measured using a MTT assay. Fibronectin expression and AMPK-signaling pathway activity were assessed using ELISA and Western blotting, respectively. The production of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinases (TIMP)-2 was evaluated using quantitative real-time RT-PCR.
  
  
  RESULTS
  Exendin-4 inhibited cell proliferation and fibronectin secretion in high glucose-induced MCs. It also caused phosphorylation of AMPK and subsequently increased the ratio of MMP-2 to TIMP-2, which resulted in the degradation of fibronectin. Exendin-4 reversed extracellular signal-regulated kinase (ERK) phosphorylation and enhanced expression of mammalian target of rapamycin (mTOR) in MCs. Moreover, the activation of the AMPK pathway by exendin-4 was induced by AICAR, which was inhibited by compound C.
  
  
  CONCLUSIONS
  Exendin-4 exerts an inhibitory effect on cell proliferation and fibronectin secretion in rat MCs, partly through AMPK activation. These results may explain some of the beneficial effects of exendin-4 on the kidney.
authors.affiliation: Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Xu
authors.forename: Mei-Ping
authors.initials: MP
authors.lastname: Guan
authors.forename: Zong-Ji
authors.initials: ZJ
authors.lastname: Zheng
authors.forename: Fang
authors.initials: F
authors.lastname: Gao
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Zeng
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Xue
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000473:pathology; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D050527:Mesangial Cells; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D013549:Sweetening Agents / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D013549:Sweetening Agents; D014688:Venoms; D000077270:Exenatide; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D005947:Glucose