Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 309, Issue 1, Pages C38-C50Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00388.2014
Keywords
tight junction; tumor necrosis factor; tubular epithelial cells; transepithelial resistance; ECIS
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN 327407]
- Kidney Foundation of Canada
- Ontario Ministry of Research and Innovation
- Li Ka Shing Scholarship
- University of Toronto open scholarship
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The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is a pathogenic factor in acute and chronic kidney disease. TNF-alpha is known to alter expression of epithelial tight junction (TJ) proteins; however, the underlying mechanisms and the impact of this effect on epithelial functions remain poorly defined. Here we describe a novel biphasic effect of TNF-alpha on TJ protein expression. In LLC-PK1 tubular cells, short-term (1-6 h) TNF-alpha treatment selectively elevated the expression of the channel-forming TJ protein claudin-2. In contrast, prolonged (>8 h) TNF-alpha treatment caused a marked downregulation in claudin-2 and an increase in claudin-1, -4, and -7. The early increase and the late decrease in claudin-2 expression involved distinct mechanisms. TNF-alpha slowed claudin-2 degradation through ERK, causing the early increase. This increase was also mediated by the EGF receptor and RhoA and Rho kinase. In contrast, prolonged TNF-alpha treatment reduced claudin-2 mRNA levels and promoter activity independent from these signaling pathways. Electric Cell-substrate Impedance Sensing measurements revealed that TNF-alpha also exerted a biphasic effect on transepithelial resistance (TER) with an initial decrease and a late increase. Thus there was a good temporal correlation between TNF-alpha -induced claudin-2 protein and TER changes. Indeed, silencing experiments showed that the late TER increase was at least in part caused by reduced claudin-2 expression. Surprisingly, however, claudin-2 silencing did not prevent the early TER drop. Taken together, the TNF-alpha -induced changes in claudin-2 levels might contribute to TER changes and could also play a role in newly described functions of claudin-2 such as proliferation regulation.
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