Antioxidative effect of p38 mitogen-activated protein kinase inhibitor in the kidney of hypertensive rat.
OBJECTIVE
Nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase is regulated by angiotensin II, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha via p38 mitogen-activated protein kinase (MAPK). We hypothesized that p38 MAPK inhibitor, FR167653, may suppress NAD(P)H oxidase and its oxygen radical production and ameliorate renal damage in Dahl salt-sensitive rats with heart failure (DSHF).


METHODS
DSHF rats were fed with 8% NaCl diet from 6 to 18 weeks old. Eleven-week-old DSHF rats received either vehicle or FR167653 (2 mg/kg per day) for 7 weeks and the renal NAD(P)H oxidase p47phox and nitric oxide synthase (NOS), superoxide production and renal damage were evaluated in comparison with the control Dahl salt-resistant rat fed with 8% NaCl diet.


RESULTS
In the kidney of DSHF rat, phosphorylated p38 MAPK was enhanced with an increased IL-1beta and TNF-alpha production compared with control rats. Treatment with FR167653 significantly suppressed p38 MAPK, IL-1beta and TNF-alpha. Renal NAD(P)H oxidase p47phox expression and superoxide production were significantly increased in the DSHF rats and treatment with FR167653 suppressed NAD(P)H oxidase expression and reduced superoxide formation. Renal endothelial and inducible NOS were reduced in DSHF rats compared with control rats, but FR167653 increased NOS and NO production in the kidney. Proteinuria, glomerulosclerosis and interstitial macrophage migration via intercellular adhesion molecule-1 (ICAM-1) were enhanced in DSHF rat and they were ameliorated by FR167653.


CONCLUSIONS
The inhibition of p38 MAPK by FR167653 reduced renal IL-1beta and TNF-alpha production and ameliorated renal damage in hypertensive rat via suppression of NAD(P)H oxidase and enhanced NO bioavailability.
Tojo
Akihiro
A
Division of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan. tojyo-2im@h.u-tokyo.ac.jp
Onozato
Maristela Lika
ML
Kobayashi
Naohiko
N
Goto
Atsuo
A
Matsuoka
Hiroaki
H
Fujita
Toshiro
T
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D016207:Cytokines / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D004791:Enzyme Inhibitors; C104334:FR 167653; D010750:Phosphoproteins; D011720:Pyrazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D048051:p38 Mitogen-Activated Protein Kinases