Anti-inflammatory effect of hepatocyte growth factor in chronic kidney disease: Targeting the inflamed vascular endothelium

Recent studies show that hepatocyte growth factor (HGF) has potent anti-inflammatory effects in multiple animal models of disease in various organ systems, including the kidney, suggesting that HGF may suppress a common proinflammatory process. The aim of this study was to examine the molecular mechanism of HGF's anti-inflammatory actions in a model of chronic kidney disease. Beginning 2 wk after subtotal nephrectomy, rats received a continuous infusion of recombinant HGF, neutralization of endogenous HGF by daily injection of an anti-HGF antibody, or preimmune IgG for an additional 2 wk. The effects on inflammation and injury were examined. HGF administration ameliorated whereas neutralizing endogenous HGF worsened renal inflammation in remnant kidneys. This was accompanied by parallel alterations in endothelial activation and inflammation, marked respectively by de novo E-selectin expression in renal vascular endothelium and leukocyte adhesion to endothelium. In vitro, HGF abrogated monocyte adhesion to TNF-alpha-activated endothelial monolayers and suppressed endothelial expression of E-selectin, which depended on NF-kappa B signaling. In addition, HGF suppressed NF-kappa B reporter gene activity that was induced by TNF-alpha and counteracted TNF-alpha-elicited NF-kappa B interaction with kappa B elements at the E-selectin gene level. Dissection of the NF-kappa B signaling cascade revealed that suppression of NF-kappa B depended on HGF's inhibitory action on NF-kappa B and I kappa B phosphorylation and I kappa B degradation. In vivo, continuous infusion of exogenous HGF markedly diminished sequestration of circulating fluorescence-labeled macrophages in the remnant kidney, mimicking the action of an E-selectin blocking antibody. These findings suggest that HGF has potent and direct anti-inflammatory effects on the basis of suppression of NF-kappa B activation and downstream endothelial inflammation.