Osteopontin--a molecule for all seasons.
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Biomedical subjects
V Ophascharoensuk
Publications and source records attributed to V Ophascharoensuk.
Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis.
BACKGROUND: Osteopontin is a macrophage adhesive protein that is expressed by renal tubules in tubulointerstitial disease. METHODS: To investigate the function of OPN, we induced tubulointerstitial disease in OPN null mutant (OPN-/-) and wild-type (OPN+/+) mice by unilateral ureteral ligation. Tissue was analyzed for macrophages (ED-1), types I and IV collagen deposition, TGF-beta expression, and for tubular and interstitial cell apoptosis. RESULTS: Obstructed kidneys from both OPN-/- and OPN+/+ mice developed hydronephrosis, tubular atrophy, interstitial inflammation and fibrosis. OPN was absent in OPN-/- kidneys but was increased in obstructed OPN+/+ kidneys. Macrophage influx, measured by computer-assisted quantitative immunostaining, was less in OPN-/- mice compared to OPN+/+ mice at day 4 (threefold, P < 0.02), day 7 (fivefold, P < 0.02), but not at day 14. Interstitial deposition of types I and IV collagen were also two- to fourfold less in obstructed OPN-/- kidneys (P < 0.02). There was also a reduction of TGF-beta mRNA expression in the interstitium at day 7 (by in situ hybridization) and a near significant 34% reduction in cortical TGF-beta activity (P = 0.06) compared to obstructed OPN+/+ kidneys at day 14. Obstructed kidneys from OPN-/- mice also had more interstitial and tubular apoptotic cells (TUNEL assay) compared to obstructed OPN+/+ mice at all time points. The ability of OPN to act as a cell survival factor was also documented by showing that the apoptosis of serum-starved NRK52E renal epithelial cells was markedly enhanced in the presence of neutralizing anti-OPN antibody. CONCLUSION: OPN mediates early interstitial macrophage influx and interstitial fibrosis in unilateral ureteral obstruction. OPN may also function as a survival factor for renal tubulointerstitial cells.
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CTL effector mechanisms: diagnostic applications.
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The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury.
The cyclin-dependent kinase inhibitor p27Kip1 controls cell proliferation in response to normal mitogenic stimuli. We show here that p27Kip1 also safeguards against excessive cell proliferation in specific pathophysiologic settings. We used experimental glomerulonephritis as a paradigm for immune mediated inflammation and ureteral obstruction as a model for non-immune mediated inflammation. Renal function was substantially decreased in nephritic p27-/- mice compared with control mice, and this was associated with increased glomerular cell proliferation, apoptosis and matrix protein accumulation. Tubular epithelial cell proliferation and apoptosis was also increased in p27-/- mice following ureteral obstruction. p27Kip1 may have a general role in protecting cells and tissues from inflammatory injury.
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Role of intrinsic renal cells versus infiltrating cells in glomerular crescent formation.
BACKGROUND: Studies were undertaken to characterize the cellular composition that occurs in glomeruli and the tubulointerstitium of a passive model of complement-independent crescentic nephritis in mice. METHODS: Glomerulonephritis was induced by the injection of antibody to whole rabbit glomeruli, and tissue was examined histologically at 7, 14 and 28 days. RESULTS: Mice developed proteinuria, glomerular crescents, and progressive glomerulosclerosis and tubulointerstitial fibrosis. The majority of the cells within the crescents appeared to be intrinsic ezrin-positive epithelial cells of visceral or parietal origin. Many of the ezrin positive cells were proliferating and expressing the PDGF receptor. Despite expression of the macrophage adhesive protein, osteopontin, the early crescents were devoid of infiltrating macrophages, T cells or myofibroblasts, which could be explained by the finding that the Bowman's capsule remained intact. Tubulointerstitial damage also occurred, and included tubular dilation and atrophy, periglomerular and patchy interstitial infiltration and interstitial fibrosis with increased interstitial deposition of type IV collagen and laminin. Interstitial infiltrating cells included macrophages, CD4+ T lymphocytes, CD8+ T lymphocytes, and activated myofibroblasts. Tubular osteopontin expression was increased in the areas of tubulointerstitial damage and was associated with interstitial macrophage infiltration. CONCLUSIONS: We describe an experimental model of complement-independent murine crescentic nephritis associated with tubulointerstitial injury. Proliferating glomerular epithelial cells are the main cellular components of the crescents in this model.
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