title: Metformin induces renal medullary interstitial cell apoptosis in type 2 diabetic mice.
abstract: OBJECTIVE
  Metformin is a first-line antidiabetic drug for type 2 diabetes (T2D) with a relatively good safety profile. Metformin activates AMP-activated protein kinase (AMPK), which is crucial in maintaining renal medullary function, with inappropriate AMPK activation facilitating renal medullary interstitial cells (RMICs) apoptosis under hypertonic challenge. The present study was to determine the effects of metformin on RMIC survival in both normal and T2D mice.
  
  
  METHODS
  Mice (C57BL/6, db/m, and db/db) were treated with 450 mg/kg metformin for 7 days and subjected to 24-h water restriction (=dehydration) before being killed. Cell apoptosis in the renal medulla was determined by the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay. Cultured RMIC were treated with 10 mmol/L metformin in the presence or absence of hypertonic stress. Cell viability was determined and the underlying mechanisms were investigated.
  
  
  RESULTS
  Metformin induced significant apoptosis of RMIC in dehydrated normal mice and both hydrated and dehydrated T2D mice. Hypertonicity increased ATP production and inhibited AMPK phosphorylation in RMIC, which was attenuated by metformin. Metformin augmented hypertonicity-induced apoptosis of RMIC, suppressed the nuclear factor-κB/cyclo-oxygenase-2 pathway, reduced reactive oxygen species production and inhibited transcriptional activation of tonicity-responsive enhancer binding protein (TonEBP) and its downstream osmoprotective gene expression.
  
  
  CONCLUSIONS
  Metformin treatment is associated with increased RMIC apoptosis in both normally hydrated and dehydrated T2D mice. The results confirm AMPK as a critical factor involved in the maintenance of RMIC viability in T2D and raise safety concerns for metformin and other AMPK-activating antidiabetic drugs in dehydrated diabetic patients.
authors.affiliation: Department of Physiology and Pathophysiology, Key Laboratory of Cardiovascular Science of the Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Senfeng
authors.initials: S
authors.lastname: Zheng
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Qifei
authors.initials: Q
authors.lastname: Han
authors.forename: Shizheng
authors.initials: S
authors.lastname: Huang
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.forename: Jialin
authors.initials: J
authors.lastname: Fu
authors.forename: Xiao
authors.initials: X
authors.lastname: Jia
authors.forename: Shengnan
authors.initials: S
authors.lastname: Du
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006982:Hypertonic Solutions / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics; D014868:Water Deprivation
chemical_list: D006982:Hypertonic Solutions; D007004:Hypoglycemic Agents; D016328:NF-kappa B; C492200:Nfat5 protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D008687:Metformin; D051546:Cyclooxygenase 2; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; apoptosis; hypertonicity; metformin; renal medullary interstitial cells; 腺苷酸-活化蛋白激酶，细胞凋亡，高渗，二甲双胍，肾髓间质细胞