title: NF-kappaB-dependent increase in intrarenal angiotensin II induced by proteinuria.
abstract: BACKGROUND
  Intrarenal activation of the renin-angiotensin system has been suggested to play a pivotal role in the progression of various renal diseases, but the regulation of each component has not been fully clarified. We investigated the roles of nuclear factor kappaB (NF-kappaB) activation in the intrarenal renin-angiotensin system changes induced by proteinuria.
  
  
  METHODS
  We used unilaterally nephrectomized rats loaded with bovine serum albumin as a model of proteinuric renal injury. Renal NF-kappaB activation was inhibited by gene transfer of the truncated form of IkappaBalpha via injection of a recombinant adenovirus vector into the renal artery, as we reported previously.
  
  
  RESULTS
  Inhibition of renal NF-kappaB activation attenuated the increases in intrarenal angiotensinogen protein (2.0-fold in rats with protein overloading and saline injection to 1.3-fold in rats with protein overloading and injection of a truncated form of IkappaBalpha) and angiotensin II (1.8-fold to 1.2-fold), and angiotensinogen mRNA. The increases in angiotensin-converting enzyme (ACE) and angiotensin II receptor type 2 were unaffected by NF-kappaB inhibition. The expression of ACE2, an enzyme that metabolizes angiotensins I and II, was decreased by 37%, and NF-kappaB inhibition abolished the decrease. Immunohistochemical analysis revealed that the angiotensinogen and ACE2 expression changes occurred mainly in proximal tubule cells (i.e., the target of adenoviral gene transfer).
  
  
  CONCLUSIONS
  These results indicate that proteinuria induces an increase in renal angiotensin II in an NF-kappaB-dependent manner. Induction of angiotensinogen and decrease in ACE2 levels may be involved in this NF-kappaB-dependent increase in angiotensin II.
authors: Department of Internal Medicine, and Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.
authors: Osamu
authors: O
authors: Takase
authors: Takeshi
authors: T
authors: Marumo
authors: Naohiko
authors: N
authors: Imai
authors: Junichi
authors: J
authors: Hirahashi
authors: Atsushi
authors: A
authors: Takayanagi
authors: Keiichi
authors: K
authors: Hishikawa
authors: Matsuhiko
authors: M
authors: Hayashi
authors: Nobuyoshi
authors: N
authors: Shimizu
authors: Toshiro
authors: T
authors: Fujita
authors: Takao
authors: T
authors: Saruta
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism; D004044:Dietary Proteins / Q000493:pharmacokinetics; D005260:Female; D020672:I-kappa B Proteins / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics; D012083:Renin / Q000235:genetics
chemical_list: D004044:Dietary Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; D000804:Angiotensin II; D000072000:NF-KappaB Inhibitor alpha; D000803:Angiotensin I; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin