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.
    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.03.004
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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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    ABSTRACT: Systemic lupus erythematosus (SLE) is a multisystemic disease, caused by a variety of factors, which lead to immunological abnormalities. Osteopontin (OPN) is a pleiotropic protein, important in bone remodeling and immune system signaling. OPN, produced by various cells, including immune cells, plays a key role in regulating T-helper 1/T-helper 2 balance, stimulating B lymphocytes to produce antibodies, regulating macrophages, neutrophils and inducing dendritic cells. OPN expression is influenced by genetic polymorphisms of its promoter, hormones and cytokines. Over expression of OPN has been associated with the pathogenesis of immune-mediated diseases. OPN has been implicated in the development of murine model of lupus and in humans with SLE. In this review, I will present current state of research on the role of OPN and OPN gene polymorphisms in pathogenesis and clinical course of SLE. A better understanding of the role of OPN in SLE will contribute to more precise diagnosis and treatment of the disease.
    Archivum Immunologiae et Therapiae Experimentalis 06/2014; 62(6). DOI:10.1007/s00005-014-0294-x · 3.18 Impact Factor
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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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    ABSTRACT: Repetitive brief ischemia and reperfusion (I/R) is associated with ventricular dysfunction in pathogenesis of murine ischemic cardiomyopathy and human hibernating myocardium. We investigated the role of matricellular protein osteopontin-1 (OPN) in murine model of repetitive I/R. One 15-min LAD-occlusion followed by reperfusion was performed daily over 3, 5, and 7 consecutive days in C57/Bl6 wildtype- (WT-) and OPN(-/-)-mice (n = 8/group). After echocardiography hearts were processed for histological and mRNA-studies. Cardiac fibroblasts were isolated, cultured, and stimulated with TGF- β 1. WT-mice showed an early, strong, and cardiomyocyte-specific osteopontin-expression leading to interstitial macrophage infiltration and consecutive fibrosis after 7 days I/R in absence of myocardial infarction. In contrast, OPN(-/-)-mice showed small, nontransmural infarctions after 3 days I/R associated with significantly worse ventricular dysfunction. OPN(-/-)-mice had different expression of myocardial contractile elements and antioxidative mediators and a lower expression of chemokines during I/R. OPN(-/-)-mice showed predominant collagen deposition in macrophage-rich small infarctions. We found lower induction of tenascin-C, MMP-9, MMP-12, and TIMP-1, whereas MMP-13-expression was higher in OPN(-/-)-mice. Cultured OPN(-/-)-myofibroblasts confirmed these findings. In conclusion, osteopontin seems to modulate expression of contractile elements, antioxidative mediators, and inflammatory response and subsequently remodel in order to protect cardiomyocytes in murine ischemic cardiomyopathy.
    BioMed Research International 05/2014; 2014:124063. DOI:10.1155/2014/124063 · 2.71 Impact Factor
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