Abstract
Endothelin-1 (ET-1) is a potent vasoconstrictor and blood pressure modulator. Renin secretion from juxtaglomerular (JG) cells is crucial for blood pressure and electrolyte homeostasis and has been shown to be modulated by ET-1; however, the cellular and molecular mechanism of this regulation is not clear. The purpose of this study was to gain a better understanding of the cellular and molecular pathways activated by ET-1 by using a renin-producing cell line As4.1. ET-1 caused an increase in As4.1 cell intracelluar Ca(2+) concentration ([Ca(2+)](i)) mediated by the ET(A) receptor as its antagonist, BQ-123, abolished the response. The nitric oxide donor nitroprusside, but not 8-bromo-cGMP, reduced the time necessary for successive ET-1 responses. Endothelin-3 had no effect on [Ca(2+)](i). ET-1 dose dependently increased total inositol phosphates with an EC(50) of 2.1 nM. ET-1 reduced renin mRNA by 68% independently of changes in message decay. With the use of a renin-luciferase reporter system in As4.1 cells, ET-1 reduced luciferase activity by 51%, suggesting that renin gene transcription is directly modified by ET-1.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium / metabolism*
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Cell Line
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Clone Cells
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Cyclic GMP / analogs & derivatives*
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Cyclic GMP / pharmacology
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Dose-Response Relationship, Drug
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Endothelin Receptor Antagonists
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Endothelin-1 / pharmacology*
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Endothelin-3 / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology*
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Inositol Phosphates / metabolism
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Juxtaglomerular Apparatus / cytology
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Juxtaglomerular Apparatus / drug effects
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Juxtaglomerular Apparatus / metabolism
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Kidney / cytology
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Kidney / drug effects
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Kidney / metabolism*
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Kidney Neoplasms
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Mice
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Mice, Transgenic
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Nitric Oxide Donors / pharmacology
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Peptides, Cyclic / pharmacology
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RNA, Messenger / metabolism
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Receptor, Endothelin A
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Renin / genetics
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Renin / metabolism*
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Second Messenger Systems / drug effects
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Second Messenger Systems / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology
Substances
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Endothelin Receptor Antagonists
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Endothelin-1
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Endothelin-3
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Inositol Phosphates
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Nitric Oxide Donors
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Peptides, Cyclic
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RNA, Messenger
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Receptor, Endothelin A
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8-bromocyclic GMP
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Renin
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Cyclic GMP
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cyclo(Trp-Asp-Pro-Val-Leu)
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Calcium