title: Tumor necrosis factor induces sodium retention in diabetic rats through sequential effects on distal tubule cells.
abstract: BACKGROUND
  Tumor necrosis factor (TNF) contributes to sodium retention during diabetes. TNF selectively stimulates sodium uptake in distal tubule cells isolated from diabetic rats, but not in cells from control rats. We propose that distal tubule cells are sensitized to acute effects of TNF during diabetes.
  
  
  METHODS
  We examined acute TNF-stimulated sodium uptake in distal tubule cells chronically cultured with exogenous TNF and in distal tubule cells freshly isolated from diabetic rats treated with a specific TNF inhibitor. We also tested the sodium transport and intracellular signaling pathway underlying TNF-induced sodium transport with pharmacologic inhibitors.
  
  
  RESULTS
  Chronic TNF exposure in vitro sensitized distal tubule cells to the acute effects of TNF in a time- and dose-dependent manner, and TNF inhibition in vivo during diabetes prevented distal tubule sensitization. TNF receptor expression was equivalent in distal tubule cells from both control and diabetic rats. In sensitized distal tubule cells, TNF-stimulated sodium uptake was blocked by amiloride and PD098059, inhibitors of epithelial sodium channels and extracellular signal-related protein kinase (ERK) activation, respectively.
  
  
  CONCLUSIONS
  TNF alters distal tubule sodium transport during diabetes through consecutive chronic and acute effects. Chronic TNF exposure leads to distal tubule sensitization that permits acute TNF-induced activation of epithelial sodium channel (ENaC). These findings are consistent with a sequential mechanism by which chronic and acute TNF actions at the distal tubule cellular level contribute to whole animal sodium retention during diabetes.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: DiPetrillo
authors.forename: Bonita
authors.initials: B
authors.lastname: Coutermarsh
authors.forename: Nicole
authors.initials: N
authors.lastname: Soucy
authors.forename: John
authors.initials: J
authors.lastname: Hwa
authors.forename: Frank
authors.initials: F
authors.lastname: Gesek
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D053503:Epithelial Sodium Channels; D000068800:Etanercept; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D053503:Epithelial Sodium Channels; D005419:Flavonoids; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D015222:Sodium Channels; D014409:Tumor Necrosis Factor-alpha; D000584:Amiloride; D012964:Sodium; D048049:Extracellular Signal-Regulated MAP Kinases; D000068800:Etanercept; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one