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  • Title: NF-kappaB-dependent increase in intrarenal angiotensin II induced by proteinuria.
    Author: Takase O, Marumo T, Imai N, Hirahashi J, Takayanagi A, Hishikawa K, Hayashi M, Shimizu N, Fujita T, Saruta T.
    Journal: Kidney Int; 2005 Aug; 68(2):464-73. PubMed ID: 16014023.
    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). CONCLUSION: 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.
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