Telmisartan inhibits both oxidative stress and renal fibrosis after unilateral ureteral obstruction in acatalasemic mice

Hitoshi Sugiyama, Mizuho Kobayashi, Da Hong Wang, Reiko Sunami, Yohei Maeshima, Yasushi Yamasaki, Noriyoshi Masuoka, Shohei Kira, Hirofumi Makino

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Abstract

Background. Reactive oxygen species are involved in many of the angiotensin II signalling pathways. We have thus investigated whether the angiotensin 1 (AT1) receptor antagonist, telmisartan, can inhibit the accelerated renal fibrosis and excess oxidative stress, which occurs after unilateral ureteral obstruction (UUO) in acatalasemic mice. Methods. The effect of daily intraperitoneal injection of telmisartan (0.1-0.3/mg/kg body weight) on the renal tubulointerstitial injury induced by UUO has been studied in homozygous acatalasemic mutant mice (C3H/AnLCsbCsb) and wild-type mice (C3H/AnLCsaCsa). We evaluated the systemic blood pressure of the mice on the seventh day. In addition, the tubulointerstitial expression of collagens type I and type IV, the p22-, p47- and p67-phox subunits of NADPH oxidase, 4-hydroxy-2-nonenal, and 4-hydroxy-2-hexenal lipid peroxidation products were assessed by immunohistochemistry. The level of apoptosis was determined by terminal deoxynucleotidyl transferase nick end-labelling analysis, while the mRNA level of the p22-, p47- and p67-phox subunits was quantified by real-time PCR. The renal content of each of the antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase was determined by specific assay. Results. Obstructed kidneys from acatalasemic mice exhibited increased tubulointerstitial deposition in dilated tubules of collagens type I and IV, lipid peroxidation products, and the p22/p47/p67-phox subunits of NADPH oxidase. The level of the p22/p47/p67-phox subunit mRNA, and of apoptosis in tubular epithelial cells, was also increased compared with those from wild-type kidneys. Treatment with telmisartan attenuated all of the changes and prevented renal fibrosis in a dose-dependent manner; despite the low dose (0.1/mg/kg). The treatment did not lower the systemic blood pressure. The catalase activity remained low in acatalasemic obstructed kidneys without compensatory upregulation of glutathione peroxidase or superoxide dismutase activity; the level of neither anti-oxidant enzymes in obstructed kidneys was affected by telmisartan. Conclusions. The AT1 receptor antagonist telmisartan ameliorated renal fibrosis after UUO by inhibition of oxidative stress, even under acatalasemic conditions.

Original languageEnglish
Pages (from-to)2670-2680
Number of pages11
JournalNephrology Dialysis Transplantation
Volume20
Issue number12
DOIs
Publication statusPublished - Dec 1 2005

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Keywords

  • Acatalasemia
  • Angiotensin II receptor antagonist
  • Apoptosis
  • Catalase
  • NADPH oxidase

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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