Protein kinase C β inhibition ameliorates experimental mesangial proliferative glomerulonephritis

Hirobumi Tokuyama, Sandra Kim, Yuan Zhang, Robyn G. Langham, Alison J. Cox, Renae M. Gow, Darren J. Kelly, Richard E. Gilbert

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Aim: Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy where therapy targeting the β isoform of this enzyme has been examined. However, PKC-β is also increased in various forms of human glomerulonephritis, including IgA nephropathy. Accordingly, we sought to examine the effects of PKC-β 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-β inhibitor, ruboxistaurin (10 mg/kg per day in chow) or vehicle. Animals were then examined 6 days later. Results: PKC-β inhibition was associated with reductions in mesangial cellularity and extracellular matrix deposition. Proteinuria was, however, unaffected. In vitro, PKC-β inhibition showed modest, dose-dependent reductions in mesangial cell 3H-thymidine and 3H-proline incorporations, indices of cell proliferation and collagen synthesis, respectively. Conclusion: The amelioration of the pathological findings of experimental mesangial proliferative glomerulonephritis by PKC-β inhibition suggests the potential clinical utility of this approach as a therapeutic strategy in non-diabetic glomerular disease. This paper describes the amelioration of the pathological findings by PKC-β inhibitor, ruboxistaurin, in Thy1.1 model of mesangial proliferative glomerulonephritis. These data, together with the demonstrated safety of ruboxistaurin in phase II-III clinical trials in diabetes, suggest that PKC-β inhibition might also be a suitable therapeutic strategy in IgA nephropathy.

Original languageEnglish
Pages (from-to)649-655
Number of pages7
JournalNephrology
Volume16
Issue number7
DOIs
Publication statusPublished - 2011 Sep

Keywords

  • IgA nephropathy
  • mesangial proliferative glomerulonephritis
  • platelet-derived growth factor
  • protein kinase C
  • ruboxistaurin

ASJC Scopus subject areas

  • Nephrology

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