Protein kinase Cbeta inhibition attenuates osteopontin expression, macrophage recruitment, and tubulointerstitial injury in advanced experimental diabetic nephropathy.
Tubulointerstitial macrophage accumulation is an important marker of prognosis that correlates closely with declining renal function in a range of human and experimental diseases, including diabetic nephropathy. These inflammatory cells are rich in the profibrotic growth factor TGF-beta such that their presence in areas of injury is frequently associated with tissue fibrosis. The migration of macrophages occurs in response to the site-specific production of chemokines, with osteopontin closely associated with their trafficking into the tubulointerstitium of the kidney. Although cell culture studies indicate that protein kinase C (PKC) mediates the expression of osteopontin, its role in the in vivo setting is unknown. Accordingly, Ren-2 control and diabetic rats that were treated with or without the specific PKC-beta isoform inhibitor ruboxistaurin (10 mg/kg per d) were examined. After 12 wk, diabetic rats showed increases in osteopontin expression in tubular epithelial cells of the cortex in association with macrophage infiltration, interstitial fibrosis, and activity of TGF-beta as indicated by the expression of its receptor activated protein phospho-Smad2 (P < 0.05 for all parameters). Ruboxistaurin treatment significantly attenuated these parameters (P < 0.05) in diabetic rats without affecting either BP or glycemic control. These findings suggest that osteopontin and macrophage accumulation may play a role in the tubulointerstitial injury in diabetic nephropathy and that inhibition of osteopontin expression may be one of the mechanisms by which inhibition of the beta-isoform of PKC confers a renoprotective effect.
Kelly
Darren J
DJ
Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia, 3065. dkelly@medstv.unimelb.edu.au
Chanty
Anna
A
Gow
Renae M
RM
Zhang
Yuan
Y
Gilbert
Richard E
RE
D000818:Animals; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects*; D008262:Macrophage Activation / Q000187:drug effects*; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use; D009395:Nephritis, Interstitial / Q000188:drug therapy; D053495:Osteopontin; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051381:Rats; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta