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NDT Advance Access published online on January 20, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn729
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Protein kinase C-β inhibition attenuates the progression of nephropathy in non-diabetic kidney disease

Darren J. Kelly1, Amanda J. Edgley1, Yuan Zhang1, Kerri Thai2, Sih Min Tan1, Alison J. Cox1, Andrew Advani2, Kim A. Connelly2, Catharine I. Whiteside3 and Richard E. Gilbert2

1 Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia 2 Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital 3 Faculty of Medicine, University of Toronto, Canada

Correspondence and offprint requests to: Richard E. Gilbert, Room 6-138, St Michael's Hospital, 61 Queen Street, Toronto, Ontario M5C 2T2, Canada. Tel: +1-4168673747; Fax: +1-4168673681; E-mail: richard.gilbert{at}utoronto.ca



  Abstract

Background. Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy where therapy targeting the β isoform of this enzyme is in advanced clinical development. However, PKC-β is also increased in various forms of human glomerulonephritis with several potentially nephrotoxic factors, other than high glucose, resulting in PKC-β activation. Accordingly, we sought to examine the effects of PKC-β inhibition in a non-diabetic model of progressive kidney disease.

Methods. Subtotally nephrectomized (STNx) rats were randomly assigned to receive either the selective PKC-β inhibitor, ruboxistaurin or vehicle. In addition to functional and structural parameters, gene expression of the podocyte slit-pore diaphragm protein, nephrin, was also assessed.

Results. STNx animals developed hypertension, proteinuria and reduced glomerular filtration rate (GFR) in association with marked glomerulosclerosis and tubulointerstitial fibrosis. Glomerular nephrin expression was also reduced. Without affecting blood pressure, ruboxistaurin treatment attenuated the impairment in GFR and reduced the extent of both glomerulosclerosis and tubulointerstitial fibrosis in STNx rats. In contrast, neither proteinuria nor the reduction in nephrin expression was improved by ruboxistaurin.

Conclusions. These findings indicate firstly that PKC-β inhibition may provide a new therapeutic strategy in non-diabetic kidney disease and secondly that improvement in GFR is not inextricably linked to reduction in proteinuria.

Keywords: glomerulosclerosis; nephrin; protein kinaseC; proteinuria; tubulointerstitial fibrosis

Received for publication: 12. 8.08
Accepted in revised form: 5.12.08


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