title: Angiotensin II receptor blocker inhibits p27Kip1 expression in glucose-stimulated podocytes and in diabetic glomeruli.
abstract: BACKGROUND
  Diabetic nephropathy is characterized by glomerular and tubular hypertrophy, and angiotensin II receptor blockers (ARBs) are known to prevent renal hypertrophy in diabetic patients.
  
  
  METHODS
  To determine the effect of ARB on podocyte p27(Kip1) mRNA and protein expression, podocytes were exposed to 5.6 mmol/L normal glucose or 25 mmol/L high glucose with or without ARB, 10(-7) mol/L L-158,809. For animal studies, streptozotocin-induced diabetic rats were left untreated or were treated with 1 mg/kg/day L-158,809 for 3 months (diabetes mellitus + ARB). Competitive reverse transcription-polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and morphometric analyses were performed.
  
  
  RESULTS
  p27(Kip1) mRNA and protein expression in podocytes exposed to high glucose and in 3-month diabetic glomeruli were significantly increased (P < 0.01). High glucose significantly increased angiotensin II levels both in cell lysates and in media compared with normal glucose (P < 0.05) and exogenous angiotensin II also increased p27(Kip1) mRNA and protein expression in podocytes. L-158,809 treatment in podocytes inhibited the increase in p27(Kip1) mRNA expression by 84%, and protein expression by 89% (P < 0.05). p27(Kip1) mRNA and protein expression in diabetic + ARB glomeruli were also significantly reduced by 78% and 85%, respectively, compared with diabetic glomeruli (P < 0.01). ARB treatment also significantly ameliorated increased glomerular p27(Kip1) expression in diabetes mellitus as assessed by immunohistochemistry (P < 0.01). The increase in glomerular volume in diabetes mellitus was also inhibited by 81% with ARB treatment (P < 0.05).
  
  
  CONCLUSIONS
  p27(Kip1) mRNA and protein expression were increased in diabetic glomeruli as well as in high glucose-stimulated podocytes, and this increment in p27(Kip1) expression was ameliorated by ARB treatment. These findings indicate that ARB treatment has an additional effect on preventing renal hypertrophy in diabetes mellitus.
authors.affiliation: Department of Internal Medicine, College of Medicine, Institute of Kidney Disease, Yonsei University, Seoul, Korea.
authors.forename: Zhong-Gao
authors.initials: ZG
authors.lastname: Xu
authors.forename: Tae-Hyun
authors.initials: TH
authors.lastname: Yoo
authors.forename: Dong-Ryeol
authors.initials: DR
authors.lastname: Ryu
authors.forename: Hyeong
authors.initials: H
authors.lastname: Cheon Park
authors.forename: Sung Kyu
authors.initials: SK
authors.lastname: Ha
authors.forename: Dae Suk
authors.initials: DS
authors.lastname: Han
authors.forename: Sharon G
authors.initials: SG
authors.lastname: Adler
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
authors.forename: Shin-Wook
authors.initials: SW
authors.lastname: Kang
mesh_terms: D000804:Angiotensin II / Q000032:analysis; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004847:Epithelial Cells / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D013311:Streptozocin; D013777:Tetrazoles / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D007093:Imidazoles; D013777:Tetrazoles; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013311:Streptozocin; C070967:L 158809; D005947:Glucose