Obstructive uropathy in the mouse: Role of osteopontin in interstitial fibrosis and apoptosis

Division of Nephrology, Department of Medicine, University of Washington, Seattle 98195, USA.
Kidney International (Impact Factor: 8.56). 09/1999; 56(2):571-80. DOI: 10.1046/j.1523-1755.1999.00580.x
Source: PubMed


Osteopontin is a macrophage adhesive protein that is expressed by renal tubules in tubulointerstitial disease.
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.
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.
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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Available from: Charles E Alpers, Jul 29, 2015
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    • "Neutralizing antibodies to OPN diminished intradermal macrophage infiltration in response to a chemotactic peptide [63] and monocyte migration into joints leading to an inhibition of rheumatoid arthritis [71]. Impaired leukocyte recruitment in OPN−/− mice has further been demonstrated in a variety of different inflammatory disease processes [39,72–76]. In all these studies, OPN−/− mice consistently exhibited diminished leukocyte recruitment at sites of inflammation demonstrating the pivotal role of OPN to regulate leukocyte attraction during inflammation. "
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    ABSTRACT: Since its first description more than 20 years ago osteopontin has emerged as an active player in many physiological and pathological processes, including biomineralization, tissue remodeling and inflammation. As an extracellular matrix protein and proinflammatory cytokine osteopontin is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Modulation of immune cell response by osteopontin has been associated with various inflammatory diseases and may play a pivotal role in the development of adipose tissue inflammation and insulin resistance. Here we summarize recent findings on the role of osteopontin in metabolic disorders, particularly focusing on diabetes and obesity.
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    • "The biological importance of OPN in IFN-a responses was emphasized by the finding that in the absence of OPN in mice, IFN-a production by pDC through TLR9 pathway was impaired (Shinohara et al. 2006). Moreover, it has been found that elevated circulating levels of OPN are associated with renal damage in the MLR/lpr mice (Miyazaki et al. 2005; Ophascharoensuk et al. 1999; Wüthrich et al. 1998). "
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    • "According to previously published data on the role of osteopontin in macrophage function [6, 22], we found significantly stronger macrophage infiltration of the ischemic myocardium in OPN−/−-mice. In contrast to previous studies, we demonstrated predominant attraction of invading macrophages to the small, nontransmural infarctions thereby contributing to the phagocytosis of dead cardiomyocytes and subsequent scar formation. "
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