Study of antiinflammatory action of hepatocyte growth factor in human kidney cells, via blockage of NfkB and the veductin of the expression of RANTES

Renal inflammation, characterized by the influx of inflammatory cells, is believed to play a critical role in the initiation and progression of a wide range of chronic kidney diseases. Here, we show that hepatocyte growth factor (HGF) inhibited renal inflammation and proinflammatory chemokine expression by disrupting nuclear factor (NF)-B signaling. In vivo, HGF gene delivery inhibited interstitial infiltration of inflammatory T cells and macrophages, and suppressed expression of both RANTES (regulated on activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 in a mouse model of obstructive nephropathy. In vitro, HGF abolished RANTES induction in human kidney epithelial cells, which was dependent on NF-B signaling. HGF did not significantly affect the phosphorylation or degradation of IB; it also did not influence the phosphorylation or nuclear translocation of p65 NF-B. However, HGF prevented p65 NF-B binding to its cognate cis-acting element in the RANTES promoter. HGF action was dependent on the activation of the phosphoinositide 3-kinase/Akt pathway, which led to the phosphorylation and inactivation of glycogen synthase kinase (GSK)-3. Suppression of GSK-3 activity mimicked HGF and abolished RANTES expression, whereas ectopic expression of GSK-3 restored RANTES induction. HGF also induced renal GSK-3 phosphorylation and inactivation after obstructive injury in vivo. These observations suggest that HGF is a potent anti-inflammatory cytokine that inhibits renal inflammation by disrupting NF-B signaling and may be a promising therapeutic agent for progressive renal disease