title: Olmesartan Prevents Microalbuminuria in db/db Diabetic Mice Through Inhibition of Angiotensin II/p38/SIRT1-Induced Podocyte Apoptosis.
abstract: OBJECTIVE
  Blockage of the renin-angiotensin II system (RAS) prevents or delays albuminuria in diabetic patients. The aim of this study was to investigate the inhibitory mechanism of the angiotensin receptor blocker olmesartan on albuminuria in a murine model of diabetic nephropathy.
  
  
  METHODS
  Male db/db diabetic mice were fed with placebo or 20 mg/kg olmesartan by daily gavage for 12 weeks. Conditionally immortalized mouse podocytes were treated with glucose, angiotensin II, olmesartan or p38 inhibitor s8307 in different experimental conditions after differentiation.
  
  
  RESULTS
  Olmesartan reduced albuminuria in db/db mice without change in body weight and glycemia. The increase of apoptotic cells and decrease of podocytes in the diabetic glomerulus were prevented by olmesartan. Moreover, olmesartan restored silent mating type information regulation 1 (SIRT1) expression in diabetic glomeruli. Furthermore, olmesartan treatment suppressed p38 phosphorylation but did not restore adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation in the diabetic glomerulus. In vitro study revealed that olmesartan prevented angiotensin II/p38/SIRT1 induced podocyte apoptosis, but it only slightly prevented high glucose/AMPK/SIRT1 induced podocyte apoptosis. In addition, the p38 inhibitor s8307 reversed SIRT1 expression and angiotensin II induced podocyte apoptosis.
  
  
  CONCLUSIONS
  Olmesartan reduced albuminuria in diabetic nephropathy through inhibiting angiotensin II/p38/SIRT1 triggered podocyte apoptosis.
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Gu
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Na
authors.initials: N
authors.lastname: Qi
authors.forename: Shuqin
authors.initials: S
authors.lastname: Mei
authors.forename: Jiejian
authors.initials: J
authors.lastname: Chen
authors.forename: Shuwei
authors.initials: S
authors.lastname: Song
authors.forename: Ying
authors.initials: Y
authors.lastname: Jing
authors.forename: Meihan
authors.initials: M
authors.lastname: Chen
authors.forename: Liangliang
authors.initials: L
authors.lastname: He
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Huimin
authors.initials: H
authors.lastname: Hu
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.forename: Changlin
authors.initials: C
authors.lastname: Mei
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000517:prevention & control*; D000804:Angiotensin II / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D050199:Podocytes / Q000473:pathology*; D056564:Sirtuin 1 / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
chemical_list: D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; C437965:olmesartan; D048051:p38 Mitogen-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1