Endothelin inhibits NPR-A and stimulates eNOS gene expression in rat IMCD cells.
We have shown in previous studies that high extracellular tonicity is associated with increased expression of the type A natriuretic peptide receptor (NPR-A) and reduced expression of the endothelial NO synthase (eNOS) gene in cultured rat inner-medullary collecting duct cells. The vasoactive peptide endothelin has been shown to be avidly expressed in this nephron segment, and to be subject to osmotic regulation. We asked whether endothelin might play a role in the control of basal or osmotically regulated NPR-A or eNOS gene expression in these cells. Although exogenous endothelin had little or no effect on basal expression of eNOS mRNA or protein or NPR-A gene expression, both the type A (BQ610) and type B (IRL1038) endothelin receptor antagonists proved capable of reducing eNOS mRNA and protein expression, and increasing levels of the NPR-A mRNA. Increased extracellular tonicity reduced endothelin mRNA accumulation in these cells (approximately 15% of control levels); however, exogenous endothelin failed to normalize osmotically increased NPR-A activity or expression, or osmotically suppressed eNOS expression. Collectively, these data demonstrate the presence of a number of independent but highly interactive local regulatory networks governing fluid and electrolyte handling in this distal nephron segment.
Ye
Qiong
Q
Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0540, USA.
Chen
Songcang
S
Gardner
David G
DG
D000818:Animals; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D007679:Kidney Medulla / Q000166:cytology*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D009842:Oligopeptides / Q000494:pharmacology; D009997:Osmotic Pressure; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; C087220:BQ 610; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A