Abstract
We studied the possible participation of endothelin-1 (ET-1) in the pathogenesis of renal damage in glycerol-induced acute renal failure (ARF). Cortical mRNA expression of ET-1 increased, peaking at 10 hr postinjury, but this did not occur in the medulla, plasma concentration and urinary excretion of ET-1 also increased in this model. There was no change in ETA receptor mRNA, whereas the ETB receptor tended to be down-regulated in the kidney after glycerol administration. In situ hybridization study demonstrated that elevated expression of prepro ET-1 was predominantly localized in cells in the proximal tubules of the nephritic kidney. The administration (30–3 mg/kg) of S-0139, (+)-disodium 27-[(E)-3-[2-[(E)-3-carboxylatoacryloylamino]-5-hydroxyphenl]acrylayloxy]-3-oxoolean-12-en-28-oate, an ETA selective antagonist, after initiation of insult offered dose-dependent prevention against ARF, demonstrating preventing of renal function impairment and mortality. These findings indicate that ET-1 participates in the pathogenesis of acute tubular injury in glycerol-induced ARF and that ETA antagonist may be useful in the treatment of some types of human ARF.
Footnotes
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Send reprint requests to: Dr. Toshikatsu Shimizu, Shionogi Research Laboratories, Shionogi & Co., Ltd., 3–1-1, Futaba-cho, Toyonaka, Osaka 561, Japan.
- Abbreviations:
- ET
- endothelin
- ETAR
- ET A receptor
- ETBR
- ET B receptor
- mRNA
- messenger ribonucleic acid
- cDNA
- complementary deoxyribonucleic acid
- RT-PCR
- reverse transcription polymerase chain reaction
- dNTPs
- mixture of dCTP, dGTP, dATP and dTTP
- dCTP
- deoxycytosinetriphosphate
- ppET-1
- prepro ET-1
- DIG
- digoxigenin
- PBS
- phosphate-buffered saline
- TE
- tris-EDTA
- DTT
- dithiothreitol
- SDS
- sodium dodecyl
- Received December 8, 1997.
- Accepted April 1, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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