ABSTRACT

Autoinduction of endothelin-1 (ET-1) has been suggested to be involved in the profound and long-lasting effects of ET-1. We examined mechanisms that underlie autoinduction of ET-1 in cultured rat glomerular mesangial cells. Incubation of mesangial cells with ET-1 resulted in an immediate and dose-dependent stimulation of preproET-1 mRNA expression as assessed by polymerase chain reaction coupled with reverse transcription. Within 1 h of exposure to ET-1 (10M), preproET-1 mRNA expression was increased to a maximal level of 465 ± 43% of the control value (p < 0.01), which was accompanied by significant stimulation of production of the immunoreactive ET-1 peptide. Nuclear run-off analysis revealed increases in the transcriptional rate of preproET-1 mRNA to 239 and 175% above the control values at 1 and 3 h of ET-1 stimulation, respectively. ET-1 also increased the stability of preproET-1 mRNA, resulting in an mRNA half-life of 60 min from 20 min seen in non-stimulated cells. Addition of an ET-specific antagonist, RES701-1, at >10M abolished ET-1 stimulation of preproET-1 mRNA (p < 0.001), whereas an ETspecific antagonist, BQ123, was without effects (up to 10M). The ET agonist, sarafotoxin S6c (10M), significantly stimulated preproET-1 mRNA expression to 201 ± 14% above controls (p < 0.01), an effect that was lessened significantly by RES701-1 (p < 0.05). RES701-1 abolished the ET-1-induced production of the ET-1 peptide (p < 0.001). Taken together, we demonstrates that in mesangial cells, autoinduction of ET-1 occurs through the ET receptor subtype via increases in both preproET-1 transcription and mRNA stability.

FOOTNOTES

*

This work was supported in part by National Institutes of Health Grants DK42159 and DK44757. Preliminary accounts of this work were presented at the 27th Annual Meeting of the American Society of Nephrology, Orlando, FL, October 26-29, 1994, and were published in abstract form ((1994) J. Am. Soc. Nephrol.5, 717). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Established Investigator of the American Heart Association. To whom correspondence should be addressed: C-4204 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232-2584. Tel.: 615-322-7931; Fax: 615-322-7929.

()

The abbreviations used are: ET, endothelin; ET and ET, endothelin receptor subtype A and B; TGF- and -, transforming growth factor- and -; RT-PCR, reverse transcription coupled with polymerase chain reaction; PBS, phosphate-buffered saline; NO, nitric oxide; DTT, dithiothreitol; bp, base pair(s).

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