TY - JOUR
T1 - Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats
AU - Nishiyama, Akira
AU - Yoshizumi, Masanori
AU - Rahman, Matlubur
AU - Kobori, Hiroyuki
AU - Seth, Dale M.
AU - Miyatake, Akira
AU - Zhang, Guo Xing
AU - Yao, Li
AU - Hitomi, Hirofumi
AU - Shokoji, Takatomi
AU - Kiyomoto, Hideyasu
AU - Kimura, Shoji
AU - Tamaki, Toshiaki
AU - Kohno, Masakazu
AU - Abe, Youichi
N1 - Funding Information:
This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science and Culture of Japan, the Research Foundation for Pharmaceutical Sciences (to Akira Nishiyama), the Uehara Memorial Foundation (to Akira Nishiyama and Hiroyuki Kobori), the National Kidney Foundation (to Hiroyuki Kobori), and the Salt Science Research Foundation (to Youichi Abe). We gratefully thank Yukiko Nagai, Kayoko Miyata (Kagawa Medical University), and Eri Hiramoto (Okayama University Medical School) for excellent technical assistance. We are also grateful to Dr. L. Gabriel Navar (Department of Physiology, Tulane University Health Sciences Center) for critical reading of the manuscript and helpful suggestions, and to Takeda Pharmaceutical Industries, Ltd., for supplying candesartan cilexetil.
PY - 2004/3
Y1 - 2004/3
N2 - Background. The mitogen-activated protein kinase (MAPK) cascade is an important intracellular mediator of angiotensin II (Ang II)-induced cell growth and differentiation. Here, we examined the effect of angiotensin II type 1 receptor (AT1) receptor blockade on renal injury and MAPK activity in Dahl salt-sensitive (DS) rats. Methods. DS rats were maintained on a high (H: 8.0%NaCl, N = 8) or low (L: 0.3%NaCl, N = 7) salt diet, or H + candesartan cilexetil (10 to 15 mg/kg/day, N = 8). Urinary protein excretion (U proteinV), renal cortical collagen content, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined after 4-week treatments. Plasma and kidney Ang II levels were measured by radioimmunoassay. Protein levels of AT1 and AT2 receptors in the renal cortical tissues were analyzed by Western-blotting analyses. MAPKs activities, including extracellular signal-regulated kinases (ERK)1/2, c-Jun NH2-terminal kinases (JNK), p38 MAPK, and BigMAPK-1 (BMK1), were measured by Western-blotting analyses or in vitro kinase assays. Results. DS/H rats showed higher mean blood pressure (MBP), Uprotein V, and renal cortical collagen content than DS/L rats. Increased ERK1/2, JNK, and BMK1 activities were observed in renal cortical tissues of DS/H rats (approximately 6.3-, 4.5-, and 2.5-fold, respectively), whereas p38 MAPK activity was unchanged. Plasma Ang II levels were significantly reduced in DS/H rats compared with DS/L rats, whereas kidney Ang II contents and AT1 receptor protein levels were similar. Candesartan did not alter MBP, but significantly reduced Uprotein V and collagen content, and ameliorated progressive sclerotic and proliferative glomerular changes. Furthermore, candesartan decreased renal tissue Ang II contents (from 216 ± 19 to 46 ± 3 fmol/mL) and ERK1/2, JNK, and BMK1 activities (-45%, -60%, and -70%, respectively) in DS/H rats. Conclusion. In DS hypertensive rats, some of the renoprotective effects of AT1 receptor blockade are accompanied by reductions in intrarenal Ang II contents and MAPK activity, which might not be mediated through arterial pressure changes.
AB - Background. The mitogen-activated protein kinase (MAPK) cascade is an important intracellular mediator of angiotensin II (Ang II)-induced cell growth and differentiation. Here, we examined the effect of angiotensin II type 1 receptor (AT1) receptor blockade on renal injury and MAPK activity in Dahl salt-sensitive (DS) rats. Methods. DS rats were maintained on a high (H: 8.0%NaCl, N = 8) or low (L: 0.3%NaCl, N = 7) salt diet, or H + candesartan cilexetil (10 to 15 mg/kg/day, N = 8). Urinary protein excretion (U proteinV), renal cortical collagen content, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined after 4-week treatments. Plasma and kidney Ang II levels were measured by radioimmunoassay. Protein levels of AT1 and AT2 receptors in the renal cortical tissues were analyzed by Western-blotting analyses. MAPKs activities, including extracellular signal-regulated kinases (ERK)1/2, c-Jun NH2-terminal kinases (JNK), p38 MAPK, and BigMAPK-1 (BMK1), were measured by Western-blotting analyses or in vitro kinase assays. Results. DS/H rats showed higher mean blood pressure (MBP), Uprotein V, and renal cortical collagen content than DS/L rats. Increased ERK1/2, JNK, and BMK1 activities were observed in renal cortical tissues of DS/H rats (approximately 6.3-, 4.5-, and 2.5-fold, respectively), whereas p38 MAPK activity was unchanged. Plasma Ang II levels were significantly reduced in DS/H rats compared with DS/L rats, whereas kidney Ang II contents and AT1 receptor protein levels were similar. Candesartan did not alter MBP, but significantly reduced Uprotein V and collagen content, and ameliorated progressive sclerotic and proliferative glomerular changes. Furthermore, candesartan decreased renal tissue Ang II contents (from 216 ± 19 to 46 ± 3 fmol/mL) and ERK1/2, JNK, and BMK1 activities (-45%, -60%, and -70%, respectively) in DS/H rats. Conclusion. In DS hypertensive rats, some of the renoprotective effects of AT1 receptor blockade are accompanied by reductions in intrarenal Ang II contents and MAPK activity, which might not be mediated through arterial pressure changes.
KW - AT receptor
KW - Angiotensin II (Ang II)
KW - Dahl salt-sensitive (DS) rats
KW - Kidney
KW - Mitogen-activated protein kinase (MAPK)
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U2 - 10.1111/j.1523-1755.2004.00476.x
DO - 10.1111/j.1523-1755.2004.00476.x
M3 - Article
C2 - 14871417
AN - SCOPUS:4644294344
VL - 65
SP - 972
EP - 981
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 3
ER -