title: Impaired natriuretic response to high-NaCl diet plus aldosterone infusion in mice overexpressing human CD39, an ectonucleotidase (NTPDase1).
abstract: Extracellular 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.
authors: Nephrology Research, Department of Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors: Yue
authors: Y
authors: Zhang
authors: Transplant Institute and Gastroenterology Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Harvard University, Boston, Massachusetts;
authors: Simon C
authors: SC
authors: Robson
authors: Nephrology Research, Department of Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors: Kaiya L
authors: KL
authors: Morris
authors: Nephrology Research, Department of Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors: Kristina M
authors: KM
authors: Heiney
authors: Immunology Research Center, Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Australia;
authors: Karen M
authors: KM
authors: Dwyer
authors: Nephrology Research, Department of Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah; Center on Aging, University of Utah Health Sciences Center, Salt Lake City, Utah; BK.Kishore@hsc.utah.edu.
authors: Bellamkonda K
authors: BK
authors: Kishore
authors: Department of Medicine, Georgetown University, Washington, DC; and Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington, District of Columbia.
authors: Carolyn M
authors: CM
authors: Ecelbarger
mesh_terms: D000450:Aldosterone / Q000097:blood*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology; D004039:Diet, Sodium-Restricted / Q000379:methods; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009318:Natriuresis / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D053503:Epithelial Sodium Channels; D049992:Sodium Chloride Symporters; D000450:Aldosterone; D012964:Sodium; D001081:Apyrase; C067869:CD39 antigen; D000254:Sodium-Potassium-Exchanging ATPase
keywords: aldosterone; ectonucleotidases; extracellular nucleotides; nucleoside triphosphate diphosphohydrolase-1; purinergic receptors; sodium transporters