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The SOD Mimetic Tempol Ameliorates Glomerular Injury and Reduces Mitogen-Activated Protein Kinase Activity in Dahl Salt-Sensitive Rats

Akira Nishiyama^*, Masanori Yoshizumi^||, Hirofumi Hitomi^*, Shoji Kagami^¶, Shuji Kondo^¶, Akira Miyatake, Megumu Fukunaga, Toshiaki Tamaki^||, Hideyasu Kiyomoto, Masakazu Kohno, Takatomi Shokoji^*, Shoji Kimura^* and Youichi Abe^*

*Department of Pharmacology, the Research Equipment Center, Integrated Medicine, and Second Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan; and Department of ^||Pharmacology and ^¶Pediatrics, The University of Tokushima School of Medicine, Tokushima, Japan

Correspondence to Dr. Akira Nishiyama, Department of Pharmacology, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Phone: +81-87-898-5111 (ext. 2502); Fax: +81-87-891-2126; E-mail: akira{at}kms.ac.jp

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_proteinV/U_crV; 20.3 ± 1.1) and a higher cortical collagen content (22 ± 1 µg/mg) than in DS/L rats (2.4 ± 0.1 and 13 ± 1 µg/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 NH₂-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_proteinV/U_crV (4.8 ± 0.4), and cortical collagen content (14 ± 1 µg/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_proteinV/U_crV (16.2 ± 1.5) and cortical collagen content (19 ± 1 µg/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.

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