Protein kinase C-beta inhibition attenuates the progression of nephropathy in non-diabetic kidney disease.
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.
Kelly
Darren J
DJ
Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia.
Edgley
Amanda J
AJ
Zhang
Yuan
Y
Thai
Kerri
K
Tan
Sih Min
SM
Cox
Alison J
AJ
Advani
Andrew
A
Connelly
Kim A
KA
Whiteside
Catharine I
CI
Gilbert
Richard E
RE
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008301:Maleimides / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000235:genetics; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008565:Membrane Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C113267:nephrin; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta