Angiotensin II receptor blocker improves tumor necrosis factor-α-induced cytotoxicity via antioxidative effect in human glomerular endothelial cells.
OBJECTIVE
Tumor necrosis factor-α (TNF-α) is known to involve the progression of renal dysfunction through its cytotoxicity and proinflammatory effects such as the induction of intercellular adhesion molecule (ICAM)-1 expression in vascular endothelial cells (ECs). Olmesartan, one of the angiotensin II type 1 receptor blockers (ARBs), has been reported to show protective effects on injured ECs by some causal factors of renal disorder other than angiotensin II. However, the effects of olmesartan on TNF-α-induced glomerular EC damage have not been investigated. In the present study, we investigated the effects of RNH-6270, an active metabolite of olmesartan, on TNF-α-induced human glomerular EC (HGEC) damage to clarify the renoprotective mechanisms of ARBs.


METHODS
Cultured HGECs were stimulated by TNF-α, and then cell viability and cytotoxicity were measured by MTT assay and lactate dehydrogenase release assay, respectively. TNF-α-induced oxidative stress was estimated by dihydroethidium assay and lucigenin chemiluminescence assay. ICAM-1 expression and the phosphorylations of mitogen-activated protein kinases were measured using Western blotting assay.


RESULTS
RNH-6270 suppressed cell death and the increase in ICAM-1 expression induced by TNF-α via the inhibition of reactive oxygen species in HGECs.


CONCLUSIONS
Our findings suggested that olmesartan might have protective effects against TNF-α-induced glomerular EC dysfunction.
Department of Pharmacology, The University of Tokushima Graduate School, Tokushima, Japan.
Yuki
Y
Izawa-Ishizawa
Keisuke
K
Ishizawa
Takumi
T
Sakurada
Masaki
M
Imanishi
Licht
L
Miyamoto
Shoko
S
Fujii
Hironori
H
Taira
Yoshitaka
Y
Kihira
Yasumasa
Y
Ikeda
Shuichi
S
Hamano
Shuhei
S
Tomita
Koichiro
K
Tsuchiya
Toshiaki
T
Tamaki
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C437965:olmesartan