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Nephrology Dialysis Transplantation
Year: 2009  |  Volume: 24  |  Issue: 6  |  Page No.: 1782 - 1790

Protein kinase C-{beta} inhibition attenuates the progression of nephropathy in non-diabetic kidney disease

D. J Kelly, A. J Edgley, Y Zhang, K Thai, S. M Tan, A. J Cox, A Advani, K. A Connelly, C. I Whiteside and R. E. Gilbert    


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.

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