Abstract
High concentrations of urea were shown to induce a paradoxical regulatory volume decrease response with K(+) channel opening and subsequent hepatocyte shrinkage (Hallbrucker, C., vom Dahl, S., Ritter, M., Lang, F., and Häussinger, D. (1994) Pflügers Arch. 428, 552-560), although the hepatocyte plasma membrane is thought to be freely permeable to urea. The underlying mechanisms remained unclear. As shown in the present study, urea (100 mmol/liter) induced within 1 min an activation of β(1) integrins followed by an activation of focal adhesion kinase, c-Src, p38(MAPK), extracellular signal-regulated kinases, and c-Jun N-terminal kinase. Because α(5)β(1) integrin is known to act as a volume/osmosensor in hepatocytes, which becomes activated in response to hepatocyte swelling, the findings suggest that urea at high concentrations induces a nonosmotic activating perturbation of this osmosensor, thereby triggering a volume regulatory K(+) efflux. In line with this, similar to hypo-osmotic hepatocyte swelling, urea induced an inhibition of hepatic proteolysis, which was sensitive to p38(MAPK) inhibition. Molecular dynamics simulations of a three-dimensional model of the ectodomain of α(5)β(1) integrin in water, urea, or thiourea solutions revealed significant conformational changes of α(5)β(1) integrin in urea and thiourea solutions, in contrast to the simulation of α(5)β(1) in water. These changes lead to an unbending of the integrin structure around the genu, which may suggest activation, whereas the structures of single domains remained essentially unchanged. It is concluded that urea at high concentrations affects hepatic metabolism through direct activation of the α(5)β(1) integrin system.
Highlights
Whereas urea synthesis and transport have been subjected to intense research over many years, little attention has been paid to potential metabolic effects of urea in liver, whose concentration in plasma is ϳ5 mmol/liter under physiological conditions but may rise to 100 mmol/liter and more in uremia
Because ␣51 integrin is known to act as a volume/osmosensor in hepatocytes, which becomes activated in response to hepatocyte swelling, the findings suggest that urea at high concentrations induces a nonosmotic activating perturbation of this osmosensor, thereby triggering a volume regulatory K؉ efflux
Activation of the Integrin System by Urea and Thiourea—In line with previous data [10], sections of normo-osmotically (305 mosmol/liter) perfused rat liver strongly immunostained for ␣51 integrin, which is predominantly located at the plasma membrane (Fig. 1)
Summary
High concentrations of urea were shown to induce a paradoxical regulatory volume decrease response with K؉ channel opening and subsequent hepatocyte shrinkage Molecular dynamics simulations of a three-dimensional model of the ectodomain of ␣51 integrin in water, urea, or thiourea solutions revealed significant conformational changes of ␣51 integrin in urea and thiourea solutions, in contrast to the simulation of ␣51 in water. These changes lead to an unbending of the integrin structure around the genu, which may suggest activation, whereas the structures of single domains remained essentially unchanged. Molecular dynamics simulations of the ectodomain of ␣51 integrin revealed significant conformational changes of the protein in urea and thiourea solutions leading to an unbending of the integrin structure, which is required for activation [12]
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