Endothelin-1 increases calcium and attenuates renin gene expression in As4.1 cells.
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.
Ryan
Michael J
MJ
Department of Physiology and Biophysics, State University of New York at Buffalo, 14214, USA. ryanm@physiology.uiowa.edu
Black
Thomas A
TA
Millard
Susan L
SL
Gross
Kenneth W
KW
Hajduczok
George
G
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002999:Clone Cells; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007295:Inositol Phosphates / Q000378:metabolism; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007680:Kidney Neoplasms; D051379:Mice; D008822:Mice, Transgenic; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D007295:Inositol Phosphates; D020030:Nitric Oxide Donors; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C016276:8-bromocyclic GMP; D012083:Renin; D006152:Cyclic GMP; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium