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

Abstract

BACKGROUND:

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

METHODS:

Subtotally nephrectomized (STNx) rats were randomly assigned to receive either the selective PKC-beta 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-beta 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.

• Authors: Darren J Kelly, Amanda J Edgley, Yuan Zhang, Kerri Thai, Sih Min Tan, Alison J Cox, Andrew Advani, Kim A Connelly, Catharine I Whiteside, Richard E Gilbert
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 24 Issue 6 Pg. 1782-90 (Jun 2009) ISSN: 1460-2385 [Electronic] England
• PMID: 19155535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indoles
• Maleimides
• Membrane Proteins
• RNA, Messenger
• Transforming Growth Factor beta
• nephrin
• ruboxistaurin
• Protein Kinase C
• Protein Kinase C beta

Topics

• Animals
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Glomerular Filtration Rate (drug effects)
• Humans
• Indoles (therapeutic use)
• Kidney (drug effects, pathology, physiopathology)
• Kidney Diseases (drug therapy, enzymology, pathology, physiopathology)
• Male
• Maleimides (therapeutic use)
• Membrane Proteins (genetics)
• Mesangial Cells (drug effects, metabolism)
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase C beta
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Transforming Growth Factor beta (pharmacology)