Osmoregulation of natriuretic peptide receptor signaling in inner medullary collecting duct. A requirement for p38 MAPK.
In the inner medullary collecting duct of the terminal nephron, the type A natriuretic peptide receptor (NPR-A) plays a major role in determining urinary sodium content. This nephron segment, by virtue of its medullary location, is subject to very high levels of extracellular tonicity. We have examined the ability of medium tonicity to regulate the activity and expression of this receptor in cultured rat inner medullary collecting duct cells. We found that NaCl (75 mm) and sucrose (150 mm), but not urea (150 mm), increased natriuretic peptide receptor activity, gene expression, and promoter activity. The osmotic stimulus also activated extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). In the latter instance the beta isoform was selectively activated. Inhibition of p38 MAPK with SB203580 blocked the osmotic induction of receptor activity and expression, as well as receptor gene promoter activity, whereas inhibition of ERK with PD98059 had no effect. Cotransfection of p38 beta MAPK together with the receptor gene promoter resulted in amplification of the osmotic stimulation of the latter, whereas cotransfection of dominant negative MKK6, but not dominant-negative MEK, completely blocked the osmotic induction of receptor promoter activity. Collectively, the data indicate that extracellular osmolality stimulates receptor activity and receptor gene expression through a specific p38 beta-dependent mechanism, raising the possibility that changes in medullary tonicity could play an important role in the regulation of renal sodium handling in the terminal nephron.
Chen
Songcang
S
Diabetes Center/Metabolic Research Unit, University of California at San Francisco, San Francisco, California 94143, USA.
Gardner
David G
DG
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007679:Kidney Medulla / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012965:Sodium Chloride / Q000494:pharmacology; D013395:Sucrose / Q000494:pharmacology; D015854:Up-Regulation; D014882:Water-Electrolyte Balance / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D012965:Sodium Chloride; D013395:Sucrose; D009320:Atrial Natriuretic Factor; D006160:Guanosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP