Protein Kinase Cβ Inhibition Attenuates Osteopontin Expression, Macrophage Recruitment, and Tubulointerstitial Injury in Advanced Experimental Diabetic Nephropathy
- 1 June 2005
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 16 (6), 1654-1660
- https://doi.org/10.1681/asn.2004070578
Abstract
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-β 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-β 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-β 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 β-isoform of PKC confers a renoprotective effect.Keywords
This publication has 37 references indexed in Scilit:
- Platelet-Derived Growth Factor Receptor Transactivation Mediates the Trophic Effects of Angiotensin II In VivoHypertension, 2004
- Osteopontin Regulation by Inorganic Phosphate Is ERK1/2-, Protein Kinase C-, and Proteasome-dependentPublished by Elsevier BV ,2003
- A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C β inhibitionAmerican Journal of Kidney Diseases, 2003
- Mast cell infiltration and chemokine expression in progressive renal disease1Kidney International, 2003
- Effects of cyclosporine in osteopontin null miceKidney International, 2002
- ForewordNephrology Dialysis Transplantation, 2002
- Osteopontin mediates hypoxia-induced proliferation of cultured mesangial cells: Role of PKC and p38 MAPKKidney International, 2000
- A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR)Kidney International, 1998
- Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats.JCI Insight, 1997
- Cellular events in the evolution of experimental diabetic nephropathyKidney International, 1995