Acute loss of renal function attenuates slow leukocyte rolling and transmigration by interfering with intracellular signaling

Acute loss of renal function reduces leukocyte recruitment into inflamed tissues, and we studied the molecular basis of this using intravital microscopy of cremaster muscle and an autoperfused flow chamber system after bilateral nephrectomy or sham operation in mice. Acute loss of renal function resulted in cessation of selectin-induced slow leukocyte rolling on E-selectin/intercellular adhesion molecule 1 (ICAM-1) and P-selectin/ICAM-1. It also reduced in vivo neutrophil extravasation (assessed by reflected light oblique transillumination) without affecting chemokine-induced arrest. This elimination of selectin-mediated slow leukocyte rolling was associated with a reduced phosphorylation of spleen tyrosine kinase, Akt, phospholipase C-γ2, and p38 MAPK. However, the levels of adhesion molecules located on the neutrophil surface were not altered. Leukocytes from critically ill patients with sepsis-induced acute kidney injury showed a significantly higher rolling velocity on E-selectin/ICAM-1- and P-selectin/ICAM-1-coated surfaces compared with patients with sepsis alone or healthy volunteers. Thus, an acute loss of renal function significantly impairs neutrophil rolling and transmigration, both in vivo and in vitro. These effects are due, in part, to decreased phosphorylation of selectin-dependent intracellular signaling pathways.