Protein kinase C beta inhibition ameliorates experimental mesangial proliferative glomerulonephritis.

摘要

AIM: Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy where therapy targeting the beta isoform of this enzyme has been examined. However, PKC-beta is also increased in various forms of human glomerulonephritis, including IgA nephropathy. Accordingly, we sought to examine the effects of PKC-beta inhibition in the Thy1.1 model of mesangial proliferative glomerulonephritis. METHODS: Following administration of monoclonal OX-7, anti-rat Thy-1.1 antibody, Male Wistar rats were randomized to receive either the PKC-beta inhibitor, ruboxistaurin (10 mg/kg per day in chow) or vehicle. Animals were then examined 6 days later. RESULTS: PKC-beta inhibition was associated with reductions in mesangial cellularity and extracellular matrix deposition. Proteinuria was, however, unaffected. In vitro, PKC-beta inhibition showed modest, dose-dependent reductions in mesangial cell (3) H-thymidine and (3) H-proline incorporations, indices of cell proliferation and collagen synthesis, respectively. CONCLUSION: The amelioration of the pathological findings of experimental mesangial proliferative glomerulonephritis by PKC-beta inhibition suggests the potential clinical utility of this approach as a therapeutic strategy in non-diabetic glomerular disease.