Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats

Akira Nishiyama, Masanori Yoshizumi, Matlubur Rahman, Hiroyuki Kobori, Dale M. Seth, Akira Miyatake, Guo Xing Zhang, Li Yao, Hirofumi Hitomi, Takatomi Shokoji, Hideyasu Kiyomoto, Shoji Kimura, Toshiaki Tamaki, Masakazu Kohno, Youichi Abe

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Abstract

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.

Original languageEnglish
Pages (from-to)972-981
Number of pages10
JournalKidney international
Volume65
Issue number3
DOIs
Publication statusPublished - 2004 Mar

Keywords

  • AT receptor
  • Angiotensin II (Ang II)
  • Dahl salt-sensitive (DS) rats
  • Kidney
  • Mitogen-activated protein kinase (MAPK)

ASJC Scopus subject areas

  • Nephrology

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    Nishiyama, A., Yoshizumi, M., Rahman, M., Kobori, H., Seth, D. M., Miyatake, A., Zhang, G. X., Yao, L., Hitomi, H., Shokoji, T., Kiyomoto, H., Kimura, S., Tamaki, T., Kohno, M., & Abe, Y. (2004). Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats. Kidney international, 65(3), 972-981. https://doi.org/10.1111/j.1523-1755.2004.00476.x