Increased Excretion of Urinary 20-HETE in Rats With Cyclosporine-Induced Nephrotoxicity

Takayuki Seki; Tsuyoshi Ishimoto; Takanobu Sakurai; Yoshiko Yasuda; Kazuo Taniguchi; Mariko Doi; Mariko Sato; Richard J. Roman; Noriyuki Miyata

doi:10.1254/jphs.FP0040574

Full Papers

Increased Excretion of Urinary 20-HETE in Rats With Cyclosporine-Induced Nephrotoxicity

Takayuki Seki, Tsuyoshi Ishimoto, Takanobu Sakurai, Yoshiko Yasuda, Kazuo Taniguchi, Mariko Doi, Mariko Sato, Richard J. Roman, Noriyuki Miyata

Author information

Takayuki Seki
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Tsuyoshi Ishimoto
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Takanobu Sakurai
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Yoshiko Yasuda
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Kazuo Taniguchi
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Mariko Doi
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Mariko Sato
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Richard J. Roman
Department of Physiology, Medical College of Wisconsin
Noriyuki Miyata
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.

Keywords: cyclosporine A, renal injury, nephrotoxicity, 20-HETE, cytochrome P450 4A

JOURNAL FREE ACCESS

2005 Volume 97 Issue 1 Pages 132-137

DOI https://doi.org/10.1254/jphs.FP0040574

View "Advance Publication" version (January 15, 2005).

Details

Abstract

The present study examined the contribution of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in cyclosporine A (CsA)-induced renal nephrotoxicity. Treatment of rats with CsA (50 mg/kg) for 9 days induced renal damage as indicated by marked increase in urine flow (from 9.0 ± 0.3 ml/day to 46.6 ± 7.1 ml/day) and a 3 – 5-fold rise in blood urea nitrogen (BUN) levels. The urinary excretion of 20-HETE increased from 164 ± 5 ng/day (N = 5) to 2432 ± 290 ng/day (N = 5, P<0.01) after 9 days of CsA treatment. The increase in the urinary excretion of 20-HETE in the CsA treated rats was highly correlated with the increase in BUN levels (r = 0.819, P<0.001) and urine volume (r = 0.832, P<0.001). Immunohistochemical examination of kidney revealed that expression of cytochrome P450 4A (CYP4A) protein was markedly enhanced in the proximal tubules of CsA-treated rats. These results indicate that CsA-induced nephrotoxicity in rats is associated with a marked elevation in the renal production of 20-HETE and that 20-HETE may contribute to the pathophysiological condition of CsA-induced nephrotoxicity.

Corresponding author

Register with J-STAGE for free!