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Hepatocyte Growth Factor Ameliorates Renal Interstitial Inflammation in Rat Remnant Kidney by Modulating Tubular Expression of Macrophage Chemoattractant Protein-1 and RANTES

Rujun Gong^*, Abdalla Rifai, Evelyn M. Tolbert^*, Purba Biswas^*, Jason N. Centracchio^* and Lance D. Dworkin^*

*Division of Renal Diseases, Department of Medicine; and Department of Pathology, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island

Correspondence to Dr. Lance D. Dworkin, Division of Renal Diseases, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. Phone: 401-444-6843; Fax: 401-444-6849; E-mail: LDworkin{at}lifespan.org

Hepatocyte growth factor (HGF) has been shown to reduce renal injury in a variety of animal models of chronic renal disease. Suggested mechanisms to explain this action include prevention of tubular cell apoptosis, blocking epithelial-to-mesenchymal transition, and promotion of extracellular matrix degradation. Inflammation is another common finding in kidneys that progress to end-stage renal failure; however, the effect of HGF on inflammation has hardly been investigated. For examining this issue, 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. HGF infusion halted the progression of proteinuria and decreased renal collagen accumulation. Renal inflammation in both glomeruli and tubulointerstitium was significantly attenuated, associated with reductions in the tubular expression of the chemokines macrophage chemoattractant protein-1 (MCP-1) and RANTES (regulated upon expression normal T cell expressed and secreted). In contrast, HGF neutralization worsened renal fibrosis, aggravated renal inflammation, and enhanced tubular expression of MCP-1 and RANTES. In vitro, HGF suppressed basal and TNF-–induced expression of these chemokines at both the mRNA and protein levels in a time- and dose-dependent manner in proximal tubular epithelial cells. HGF also blunted TNF-–induced nuclear translocation and activation of NF-B, a pivotal transcription factor that regulates chemokine expression. Immunohistochemistry showed that activated NF-B was evident in tubules in remnant kidneys and increased remarkably with anti-HGF treatment. HGF infusion markedly suppressed expression of activated NF-B in remnant kidneys. These findings suggest that the beneficial effect of HGF in chronic renal disease is attributable, at least in part, to a direct anti-inflammatory action, likely via NF-B, on tubular epithelial cells.

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