Abstract. 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

Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) regulates a variety of endothelial and immune cell biological responses. PECAM-1-null mice exhibit prolonged and increased permeability after inflammatory insults. We observed that in PECAM-1-null endothelial cells (ECs), beta-catenin remained tyrosine phosphorylated, coinciding with a sustained increase in permeability. Src homology 2 domain containing phosphatase 2 (SHP-2) association with beta-catenin was diminished in PECAM-1-null ECs, suggesting that lack of PECAM-1 inhibits the ability of this adherens junction component to become dephosphorylated, promoting a sustained increase in permeability. beta-Catenin/Glycogen synthase kinase 3 (GSK-3beta) association and beta-catenin serine phosphorylation levels were increased and beta-catenin expression levels were reduced in PECAM-1-null ECs. Glycogen synthase kinase 3 (GSK-3beta) serine phosphorylation (inactivation) was blunted in PECAM-1-null ECs after histamine treatment or shear stress. Our data suggest that PECAM-1 serves as a critical dynamic regulator of endothelial barrier permeability. On stimulation by a vasoactive substance or shear stress, PECAM-1 became tyrosine phosphorylated, enabling recruitment of SHP-2 and tyrosine-phosphorylated beta-catenin to its cytoplasmic domain, facilitating dephosphorylation of beta-catenin, and allowing reconstitution of adherens junctions. In addition, PECAM-1 modulated the levels of beta-catenin by regulating the activity of GSK-3beta, which in turn affected the serine phosphorylation of beta-catenin and its proteosomal degradation, affecting the ability of the cell to reform adherens junctions in a timely fashion.

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a 130-kd member of the immunoglobulin superfamily of proteins, expressed on endothelial cells, leukocytes, and platelets. Antibody-blocking studies have implicated it in modulating leukocyte transmigration and angiogenesis. However, the generation of the PECAM-1 knockout mouse has shown that its function can be compensated for by similarly acting proteins because most acute inflammatory models proceed in a comparable manner in wild-type and knockout animals. We decided to examine the function of PECAM-1 in the chronic process of foreign body inflammation. We show that PECAM-1-deficient mice exhibit attenuated neutrophil infiltration in and around a subcutaneous polyvinyl acetyl implant. Bone marrow engraftment studies indicate that the lack of CD31 expression on the endothelium determines the diminished leukocyte accumulation in the knockout implants. Specifically, we find that decreased angiogenesis (as manifested by lower vessel density, decreased hemoglobin content, and less laminin deposition) correlates with lower neutrophil accumulation in the knockout animals. This study indicates that the absence of endothelial PECAM-1 results in decreased angiogenesis and therefore in diminished delivery of leukocytes to the foreign body implants.