NF-kappaB-dependent increase in intrarenal angiotensin II induced by proteinuria.
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.
Takase
Osamu
O
Department of Internal Medicine, and Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.
Marumo
Takeshi
T
Imai
Naohiko
N
Hirahashi
Junichi
J
Takayanagi
Atsushi
A
Hishikawa
Keiichi
K
Hayashi
Matsuhiko
M
Shimizu
Nobuyoshi
N
Fujita
Toshiro
T
Saruta
Takao
T
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
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