title: Osmoregulation of endothelial nitric-oxide synthase gene expression in inner medullary collecting duct cells. Role in activation of the type A natriuretic peptide receptor.
abstract: Previously, we showed that increased extracellular tonicity promotes increased type A natriuretic peptide receptor (NPR-A) expression through a p38 MAPKbeta pathway in inner medullary collecting duct cells. The endothelial and inducible nitric-oxide synthase (eNOS and iNOS respectively) genes are also expressed in this nephron segment and are thought to play a role in regulating urinary sodium concentration. We sought to determine whether changes in tonicity might regulate NOS gene expression, and if so, whether these latter changes might be linked mechanistically to the increase in NPR-A gene expression. Increased extracellular tonicity effected a time-dependent reduction in eNOS and iNOS protein levels, eNOS mRNA levels, and eNOS gene promoter activity over the first 8 h of the incubation. Although levels of the eNOS mRNA and promoter activity had returned to normal after 24 h, eNOS protein levels remained low at 24-36 h, and recovery was not complete even at 48 h. The decrease in eNOS expression was signaled in large part through a p38 MAPK-dependent mechanism. Reduction in eNOS expression together with the concomitant decline in intracellular cyclic GMP levels appears to account for a significant portion of the p38 MAPK-dependent osmotic stimulation of NPR-A gene expression noted previously. Collectively, these findings support the existence of a complex regulatory circuitry in the cells of the inner medullary collecting duct linking two independent cyclic GMP-generating signal transduction systems involved in regulation of urinary sodium concentration.
authors.affiliation: Diabetes Center/Metabolic Research Unit and Department of Medicine, University of California, San Francisco 94143-0540, California, USA.
authors.forename: Songcang
authors.initials: S
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.forename: Hope D
authors.initials: HD
authors.lastname: Intengan
authors.forename: Michael
authors.initials: M
authors.lastname: Humphreys
authors.forename: David G
authors.initials: DG
authors.lastname: Gardner
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D049452:Green Fluorescent Proteins; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007679:Kidney Medulla / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000201:enzymology* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D009995:Osmosis; D011725:Pyridines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D008164:Luminescent Proteins; D011725:Pyridines; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D012965:Sodium Chloride; D012313:RNA; D012964:Sodium; D008156:Luciferases; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP; C093642:SB 203580