title: The SOD mimetic tempol ameliorates glomerular injury and reduces mitogen-activated protein kinase activity in Dahl salt-sensitive rats.
abstract: It was shown recently that renal injury in Dahl salt-sensitive (DS) hypertensive rats is accompanied by mitogen-activated protein kinase (MAPK) activation. The present study was conducted to elucidate the contribution of reactive oxygen species to MAPK activities and renal injury in DS rats. DS rats were maintained on high salt (H; 8.0% NaCl; n = 7) or low salt (L; 0.3% NaCl; n = 6) diets; H + a superoxide dismutase mimetic, tempol (3 mmol/L in drinking water; n = 8); or H + hydralazine (0.5 mmol/L in drinking water; n = 8) for 4 wk. Mean BP (MBP) in DS/H and DS/L rats was 185 +/- 7 and 113 +/- 3 mmHg, respectively. DS/H rats showed a higher ratio of urinary protein excretion and creatinine (U(protein)V/U(cr)V; 20.3 +/- 1.1) and a higher cortical collagen content (22 +/- 1 micro g/mg) than in DS/L rats (2.4 +/- 0.1 and 13 +/- 1 micro g/mg, respectively). The expression of p22-phox and Nox-1, essential components of NAD(P)H oxidase, in renal cortical tissue was approximately threefold higher in DS/H rats than in DS/L rats. Increased activities of renal cortical MAPK, including extracellular signal-regulated kinases (ERK) 1/ERK2 and c-Jun NH(2)-terminal kinases (JNK) were also observed in DS/H rats by 7.0 +/- 0.7- and 4.3 +/- 0.2-fold, respectively. Tempol treatment significantly decreased MBP (128 +/- 3 mmHg), U(protein)V/U(cr)V (4.8 +/- 0.4), and cortical collagen content (14 +/- 1 micro g/mg) and normalized ERK1/ERK2 and JNK activities in DS/H rats. Histologically, tempol markedly ameliorated progressive sclerotic and proliferative glomerular changes in DS/H rats. Hydralazine-treated DS/H rats showed similar MBP (127 +/- 5 mmHg) to tempol-treated DS/H rats. Hydralazine also decreased U(protein)V/U(cr)V (16.2 +/- 1.5) and cortical collagen content (19 +/- 1 micro g/mg) in DS/H rats. However, these values were significantly higher than those of tempol-treated rats. Furthermore, although hydralazine significantly reduced JNK activity (-56 +/- 3%), ERK1/ERK2 activities were unaffected. These data suggest that reactive oxygen species, generated by NAD(P)H oxidase, contribute to the progression of renal injury through ERK1/ERK2 activation in DS/H hypertensive rats.
authors.affiliation: Department of Pharmacology, Kagawa Medical University, Kagawa, Japan. akira@kms.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Shoji
authors.initials: S
authors.lastname: Kagami
authors.forename: Shuji
authors.initials: S
authors.lastname: Kondo
authors.forename: Akira
authors.initials: A
authors.lastname: Miyatake
authors.forename: Megumu
authors.initials: M
authors.lastname: Fukunaga
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Takatomi
authors.initials: T
authors.lastname: Shokoji
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Youichi
authors.initials: Y
authors.lastname: Abe
mesh_terms: D000818:Animals; D003094:Collagen / Q000652:urine; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D013113:Spin Labels; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D003497:Cyclic N-Oxides; D013113:Spin Labels; D003094:Collagen; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C001803:tempol