title: Molecular signaling mediated by angiotensin II type 1A receptor blockade leading to attenuation of renal dysfunction-associated heart failure.
abstract: BACKGROUND
  In patients with end-stage renal disease, angiotensin II type 1A receptor (AT1) blockade attenuates the associated cardiac dysfunction. We investigated the molecular signaling mediating that effect.
  
  
  RESULTS
  We used 5/6 nephrectomy to induce significant renal dysfunction in AT1 knockout (AT1KO) and wild-type mice (WT). Twelve weeks after nephrectomy, WT showed significant left ventricular dilation and dysfunction that were accompanied by cardiomyocyte hypertrophy, fibrosis, and reduced capillary density. All of these effects were significantly mitigated in AT1KO. Nephrectomy led to upregulation of myocardial expression of AT1, transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and phosphorylated Akt (p-Akt), and also led to increased oxidative damage in cardiomyocytes. In AT1KO, TGF-beta1, TIMP-1, oxidative damage levels were lower, whereas MMPs and p-Akt levels were higher. Treating nephrectomized WT mice with valsartan (an AT1 blocker), but not hydralazine, improved cardiac function and altered molecular signaling in a manner similar to that seen in AT1KO mice. Notably, AT1 expression was downregulated in valsartan-treated but not hydralazine-treated hearts.
  
  
  CONCLUSIONS
  These findings provide novel insight into the mechanism underlying the beneficial effects of AT1 blockade on cardiac function in a model of renal dysfunction-associated heart failure.
authors: Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
authors: Yiwen
authors: Y
authors: Li
authors: Genzou
authors: G
authors: Takemura
authors: Hideshi
authors: H
authors: Okada
authors: Shusaku
authors: S
authors: Miyata
authors: Rumi
authors: R
authors: Maruyama
authors: Masayasu
authors: M
authors: Esaki
authors: Hiromitsu
authors: H
authors: Kanamori
authors: Longhu
authors: L
authors: Li
authors: Atsushi
authors: A
authors: Ogino
authors: Takamasa
authors: T
authors: Ohno
authors: Takehito
authors: T
authors: Kondo
authors: Munehiro
authors: M
authors: Nakagawa
authors: Shinya
authors: S
authors: Minatoguchi
authors: Takako
authors: T
authors: Fujiwara
authors: Hisayoshi
authors: H
authors: Fujiwara
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy / Q000009:adverse effects; D018384:Oxidative Stress / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000097:blood* / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013777:Tetrazoles / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D000068756:Valsartan; D004247:DNA; D003404:Creatinine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D014633:Valine