Abstract
During endotoxemia, the ATP-dependent drug efflux pump P-glycoprotein (Abcb1/P-gp) is upregulated in kidney proximal tubule epithelial cells. The signaling pathway through which lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α) regulates P-gp expression and activity was investigated further in the present study. Exposure of rat kidney proximal tubule cells to TNF-α alone or TNF-α and LPS increased P-gp gene and protein expression levels and efflux activity, suggesting de novo P-gp synthesis. Upon exposure to TNF-α in combination with LPS, P-gp activity in renal proximal tubule cells is increased under influence of nitric oxide (NO) produced by inducible NO synthase. Upon exposure to TNF-α alone, P-gp upregulation seems to involve TLR4 activation and nuclear factor kappaB (NF-κB) translocation, a pathway that is likely independent of NO. These findings indicate that at least two pathways regulate P-gp expression in the kidney during endotoxemia.
Highlights
P-glycoprotein (Abcb1/P-gp) is a member of the ATP binding cassette (ABC) superfamily and is able to transport a broad range of uncharged and cationic compounds
Our findings indicate that exposure to tumor necrosis factor-α (TNF-α) in combination with LPS increases P-gp activity in renal proximal tubule cells under influence of nitric oxide (NO) produced by inducible NO-synthase (iNOS)
We observed an upregulation in Abcb1b expression after exposure to TNF-α, LPS, or a combination of TNF-α and LPS (Figure 1(d)), which was accompanied by an increase in Pgp protein expression (Figure 1(e)), suggesting de novo P-gp synthesis
Summary
P-glycoprotein (Abcb1/P-gp) is a member of the ATP binding cassette (ABC) superfamily and is able to transport a broad range of uncharged and cationic compounds. Using killifish renal proximal tubules, we found previously that NO has a regulatory role in the transport activity of multidrug resistance protein 2 (Abcc2/Mrp2) via an intracellular signaling pathway in response to the in vitro action of several nephrotoxic chemicals [4]. This pathway involved at least endothelin (ET) release, binding to the basolateral ETB receptor, and activation of NOS, soluble guanylyl cyclase (sGC) and protein kinase C (PKC) [5]. The inflammatory mediator, tumor necrosis factor—alpha (TNF-α) signalled through the TNF-receptor 1 (TNFR1) to increase P-gp expression and transport activity by triggering the ET-NOSPKC pathway, activating the nuclear factor kappaB, NF-κB [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
