Angiotensin II receptor blocker inhibits tumour necrosis factor-alpha-induced cell damage in human renal proximal tubular epithelial cells.
OBJECTIVE
We investigated the effect of angiotensin II (AII) type 1 (AT1) and angiotensin II type 2 (AT2) receptor blockers on tumour necrosis factor alpha (TNF-alpha)-induced cell damage in human renal proximal tubular epithelial cells (RPTEC).


METHODS
The lactate dehydrogenase (LDH) and N-acetyl-beta-glucosaminidase (NAG) release into the medium after TNF-alpha treatment in RPTEC were determined using modified commercial procedures. In addition, the levels of caspase 3/7 activity in RPTEC were measured after TNF-alpha treatment with AlphaTau1 or AT2 receptor blockers. Finally we investigated the change of p22phox protein levels after TNF-alpha with AlphaTau1 or AT2 receptor blockers in RPTEC.


RESULTS
Tumour necrosis factor alpha (10(-8) mol/L) significantly increased LDH and NAG release into the medium from RPTEC. AlphaTau1 receptor blockers, olmesartan and valsartan (10(-9)-10(-6) mol/L) showed a significant reduction on TNF-alpha-induced LDH and NAG release in RPTEC. AT2 receptor blocker, PD123319 (10(-7)-10(-5) mol/L) also decreased TNF-alpha-induced LDH and NAG release in RPTEC. Blockade of both AlphaTau1 and AT2 receptor indicated additional reduction on TNF-alpha-induced LDH and NAG release. TNF-alpha (10(-8) mol/L) treatment showed small but significant increases of caspase 3/7 activity in RPTEC, and AT1 and AT2 receptor blockers (10(-8) mol/L) comparably decreased TNF-alpha-induced caspase 3/7 activity. Significant increases of p22phox protein levels were observed in TNF-alpha-treated group in RPTEC. However, only AlphaTau1 (10(-8) mol/L) but not AT2 (10(-5) mol/L) receptor blocker significantly decreased TNF-alpha-induced p22phox protein levels.


CONCLUSIONS
The present study demonstrates that TNF-alpha induces renal tubular cell damage in RPTEC and AT1/AT2 receptor blockers showed cytoprotective effects probably via at least partly different mechanism.
Kagawa
Toru
T
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Nankoku, Japan. kagawat@kochi-u.ac.jp
Takao
Toshihiro
T
Horino
Taro
T
Matsumoto
Reiko
R
Inoue
Kousuke
K
Morita
Tatsuhito
T
Hashimoto
Kozo
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005944:Glucosamine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D047888:Receptors, Tumor Necrosis Factor, Type I; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; C073402:PD 123319; C098108:N-acetylglucopyranosylamine; D000068756:Valsartan; C437965:olmesartan; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; C086986:CYBA protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D014633:Valine; D005944:Glucosamine