Increased excretion of urinary 20-HETE in rats with cyclosporine-induced nephrotoxicity.
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.
Seki
Takayuki
T
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama-city, Japan.
Ishimoto
Tsuyoshi
T
Sakurai
Takanobu
T
Yasuda
Yoshiko
Y
Taniguchi
Kazuo
K
Doi
Mariko
M
Sato
Mariko
M
Roman
Richard J
RJ
Miyata
Noriyuki
N
D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D042926:Cytochrome P-450 CYP4A / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006893:Hydroxyeicosatetraenoic Acids / Q000009:adverse effects / Q000652:urine*; D007274:Injections, Intraperitoneal; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced* / Q000652:urine*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014556:Urine / Q000737:chemistry / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects / Q000502:physiology
D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D016572:Cyclosporine; D003404:Creatinine; D042926:Cytochrome P-450 CYP4A