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.
Conclusion: 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.