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Endothelin-1 increases calcium and attenuates renin gene expression in As4.1 cells
Michael J Ryan1, Thomas A Black, Susan L Millard
1Department of Physiology and Biophysics, State University of New York at Buffalo, 14214, USA. ryanm@physiology.uiowa.edu
Insights
Endothelin-1 (ET-1) influences blood pressure by affecting renin secretion from juxtaglomerular cells. This study reveals ET-1 directly reduces renin gene transcription via the ET(A) receptor pathway.
Area of Science:
- Cardiovascular Physiology
- Renal Physiology
- Molecular Endocrinology
Background:
- Endothelin-1 (ET-1) is a key regulator of blood pressure and vascular tone.
- Juxtaglomerular (JG) cell renin secretion is vital for maintaining blood pressure and electrolyte balance.
- The precise cellular and molecular mechanisms by which ET-1 modulates renin secretion remain unclear.
Purpose of the Study:
- To elucidate the cellular and molecular pathways through which ET-1 affects renin production.
- To investigate the role of intracellular calcium and signaling cascades in ET-1's action on renin-secreting cells.
Main Methods:
- Utilized the As4.1 renin-producing cell line for experimental studies.
- Measured intracellular calcium ([Ca(2+)](i)) concentrations and inositol phosphate levels.
- Assessed renin mRNA levels and transcriptional activity using a renin-luciferase reporter system.
Main Results:
- ET-1 significantly increased intracellular calcium in As4.1 cells, mediated by the ET(A) receptor.
- ET-1 dose-dependently elevated total inositol phosphates, indicating activation of phospholipase C.
- ET-1 reduced renin mRNA levels by 68% and decreased renin gene transcription by 51%.
Conclusions:
- ET-1 directly inhibits renin gene transcription in JG cells through the ET(A) receptor.
- The study clarifies a key molecular mechanism linking ET-1 signaling to renin regulation.
- Findings provide insights into the complex interplay between vasoconstrictors and the renin-angiotensin system.
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.