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Impaired natriuretic response to high-NaCl diet plus aldosterone infusion in mice overexpressing human CD39, an ectonucleotidase (NTPDase1)
journal contribution
posted on 2015-06-01, 00:00 authored by Yue Zhang, Simon C Robson, Kaiya L Morris, Kristina M Heiney, Karen DwyerKaren Dwyer, Bellamkonda K Kishore, Carolyn M EcelbargerExtracellular nucleotides acting through P2 receptors facilitate natriuresis. To define how purinergic mechanisms are involved in sodium homeostasis, we used transgenic (TG) mice that globally overexpress human CD39 (hCD39, NTPDase1), an ectonucleotidase that hydrolyzes extracellular ATP/ADP to AMP, resulting in an altered extracellular purine profile. On a high-sodium diet (HSD, 3.5% Na(+)), urine volume and serum sodium were significantly higher in TG mice but sodium excretion was unaltered. Furthermore, TG mice showed an attenuated fall in urine aldosterone with HSD. Western blot analysis revealed significantly lower densities (∼40%) of the β-subunit of the epithelial sodium channel (ENaC) in medulla, and the major band (85-kDa) of γ-ENaC in TG mice cortex. To evaluate aldosterone-independent differences, in a second experiment, aldosterone was clamped by osmotic minipump at 20 μg/day, and mice were fed either an HSD or a low-sodium diet (LSD, 0.03% Na(+)). Here, no differences in urine volume or osmolality, or serum aldosterone were found, but TG mice showed a modest, yet significant impairment in late natriuresis (days 3 and 4). Several major sodium transporters or channel subunits were differentially expressed between the genotypes. HSD caused a downregulation of Na-Cl cotransporter (NCC) in both genotypes; and had higher cortical levels of NCC, Na-K-ATPase (α-1 subunit), and α- and γ-ENaC. The Na-K-2Cl cotransporter (NKCC2) was downregulated by HSD in wild-type mice, but it increased in TG mice. In summary, our data support the concept that extracellular nucleotides facilitate natriuresis; they also reveal an aldosterone-independent downregulation of major renal sodium transporters and channel subunits by purinergic signaling.
History
Journal
American journal of physiology. Renal physiologyVolume
308Issue
12Pagination
F1398 - F1408Publisher
American Physiological SocietyLocation
Bethesda, Md.Publisher DOI
ISSN
0363-6127eISSN
1522-1466Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2015, American Physiological SocietyUsage metrics
Keywords
aldosteroneectonucleotidasesextracellular nucleotidesnucleoside triphosphate diphosphohydrolase-1purinergic receptorssodium transportersAnimalsAntigens, CDApyraseBlood PressureDiet, Sodium-RestrictedEpithelial Sodium ChannelsHumansMiceNatriuresisSodiumSodium Chloride SymportersSodium-Potassium-Exchanging ATPaseScience & TechnologyLife Sciences & BiomedicinePhysiologyUrology & NephrologyCOLLECTING DUCTTRANSGENIC MICEP2 RECEPTORSTRANSPORTECTOENZYMESDISEASEKIDNEYNA+INFLAMMATIONINHIBITIONPhysiology
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