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

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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1782-1790
Number of pages9
JournalNephrology Dialysis Transplantation
Volume24
Issue number6
DOIs
Publication statusPublished - Jun 2009
Externally publishedYes

Keywords

  • Glomerulosclerosis
  • Nephrin
  • Protein kinase C
  • Proteinuria
  • Tubulointerstitial fibrosis

Cite this

Kelly, Darren J. ; Edgley, Amanda J. ; Zhang, Yuan ; Thai, Kerri ; Tan, Sih Min ; Cox, Alison J. ; Advani, Andrew ; Connelly, Kim A. ; Whiteside, Catharine I. ; Gilbert, Richard E. / Protein kinase C-β inhibition attenuates the progression of nephropathy in non-diabetic kidney disease. In: Nephrology Dialysis Transplantation. 2009 ; Vol. 24, No. 6. pp. 1782-1790.
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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 kinase C, Proteinuria, Tubulointerstitial fibrosis",
author = "Kelly, {Darren J.} and Edgley, {Amanda J.} and Yuan Zhang and Kerri Thai and Tan, {Sih Min} and Cox, {Alison J.} and Andrew Advani and Connelly, {Kim A.} and Whiteside, {Catharine I.} and Gilbert, {Richard E.}",
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Kelly, DJ, Edgley, AJ, Zhang, Y, Thai, K, Tan, SM, Cox, AJ, Advani, A, Connelly, KA, Whiteside, CI & Gilbert, RE 2009, 'Protein kinase C-β inhibition attenuates the progression of nephropathy in non-diabetic kidney disease' Nephrology Dialysis Transplantation, vol. 24, no. 6, pp. 1782-1790. https://doi.org/10.1093/ndt/gfn729

Protein kinase C-β inhibition attenuates the progression of nephropathy in non-diabetic kidney disease. / Kelly, Darren J.; Edgley, Amanda J.; Zhang, Yuan; Thai, Kerri; Tan, Sih Min; Cox, Alison J.; Advani, Andrew; Connelly, Kim A.; Whiteside, Catharine I.; Gilbert, Richard E.

In: Nephrology Dialysis Transplantation, Vol. 24, No. 6, 06.2009, p. 1782-1790.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Protein kinase C-β inhibition attenuates the progression of nephropathy in non-diabetic kidney disease

AU - Kelly, Darren J.

AU - Edgley, Amanda J.

AU - Zhang, Yuan

AU - Thai, Kerri

AU - Tan, Sih Min

AU - Cox, Alison J.

AU - Advani, Andrew

AU - Connelly, Kim A.

AU - Whiteside, Catharine I.

AU - Gilbert, Richard E.

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N2 - 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.

AB - 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.

KW - Glomerulosclerosis

KW - Nephrin

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