Possible involvement of intracellular angiotensin II receptor in high-glucose-induced damage in renal proximal tubular cells.
BACKGROUND
Recent studies have identified high glucose as a potent stimulus for the intracellular synthesis of angiotensin II. However, the exact roles of angiotensin II and angiotensin II type 1 receptor blockers (ARB) in high-glucose-induced renal tubular function remain unclear.


METHODS
N-Acetyl-beta-glucosaminidase (NAG), angiotensin II and 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations in renal proximal tubular epithelial cells (RPTECs) with or without high glucose/ARB were determined using a modified commercial procedure. The changes of p22phox and cytoplasmic inhibitory kappa B (IkB) protein levels in RPTECs were measured using Western blotting.


RESULTS
High-glucose treatment (4x10-2 mol/L) significantly increased NAG release, angiotensin II concentrations in cell lysates and 8-OHdG and p22phox protein levels compared with those in regular glucose medium (1.75x10(-2) mol/L). ARBs (candesartan, olmesartan or valsartan; 1x10(-9)-10(-7) mol/L) showed a significant reduction in high-glucose-induced NAG, 8-OHdG and p22phox protein levels in RPTECs. Significant decreases of cytoplasmic IkB protein levels were observed in the high-glucose-treated group in RPTECs. ARBs markedly reversed high-glucose-induced reduction of IkB protein levels in RPTECs.


CONCLUSIONS
ARBs reduce high-glucose-induced oxidative stress in RPTECs possibly via blockade of intracellular as well as extracellular AT1 receptor signaling, which possibly protects renal tubular cell function during diabetic nephropathy.
Takao
Toshihiro
T
Division of Community Medicine, Department of Community Nursing, Kochi Medical School, Nankoku, Japan. takaot@kochi-u.ac.jp
Horino
Taro
T
Kagawa
Toru
T
Matsumoto
Reiko
R
Shimamura
Yoshiko
Y
Ogata
Koji
K
Inoue
Kousuke
K
Taniguchi
Yoshinori
Y
Taguchi
Takafumi
T
Morita
Tatsuhito
T
Terada
Yoshio
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005947:Glucose / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011945:Receptors, Angiotensin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048828:beta-N-Acetyl-Galactosaminidase / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D011945:Receptors, Angiotensin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019255:NADPH Oxidases; C086986:CYBA protein, human; D048828:beta-N-Acetyl-Galactosaminidase; D003849:Deoxyguanosine; D005947:Glucose