[Role of thrombin and its receptor in the pathogenesis of severe forms of human glomerulonephritis with fibrin deposits].

For the first time, a functional thrombin receptor has been found in human glomeruli by immunohistochemistry using a specific monoclonal antibody directed against extracellular N-terminus. This receptor is constitutively expressed in normal human kidney. The 3 glomerular cell types, endothelial, mesangial and epithelial cells, are positively stained as are the endothelial cells of renal arteries. By in situ hybridization using a digoxigenin-labelled cDNA probe specific for thrombin receptor, the thrombin receptor mRNA was found to have the same distribution. A lighter staining of glomerular endocapillary cells was observed in cases of thrombotic microangiopathy and extracapillary glomerulonephritis. 2 renal diseases associated with in situ thrombin generation and fibrin formation whereas by in situ hybridization, the thrombin receptor mRNA was overexpressed. To understand the discrepancy between the surface expression of thrombin receptor antigen in normal and fibrin-related glomerulopathies, we studied the internalization of thrombin receptor in human mesangial cells. We found that thrombin and thrombin agonist peptides induce homologous internalization of thrombin receptor in a dose-dependent manner. In addition, a dose-dependent loss of cell surface thrombin receptor is induced by phorbol-12-myristate-13-acetate (PMA), suggesting that thrombin receptor undergoes heterologous internalization in response to PMA. The homologous internalization of the thrombin receptor is not mediated by protein kinase C activation. Taken together, the results suggest that thrombin receptor is internalized through at least 2 different pathways.