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

Ophascharoensuk, Vuddhidej; Giachelli, Cecilia M.; Gordon, Katherine; Hughes, Jeremy; Pichler, Raimund; Brown, Paul A.J.; Liaw, Lucy; Schmidt, Rodney A.; Shankland, Stuart J.; Alpers, Charles E.; Couser, William G.; Johnson, Richard J.

doi:10.1046/j.1523-1755.1999.00580.x

Cited by 274 publications

(242 citation statements)

References 35 publications

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“…The gene is expressed in a number of nervous tissues including the hindbrain, cerebellum, brainstem, spinal cord, and some parts of the peripheral nervous system (Mark et al 1988;Shin et al 1999;Ichikawa et al 2000;Ju et al 2000;Lee et al 2001;Marsh et al 2007). The neuronal phenotype of OPN null mice has not been thoroughly examined, but the lung, heart and kidney of mutant mice show increased fibrosis and apoptosis (Ophascharoensuk et al 1999;Berman et al 2004;Zohar et al 2004). The inner ear phenotype of the null mice has not been examined either.…”

Section: Introductionmentioning

confidence: 99%

Osteopontin is not Critical for Otoconia Formation or Balance Function

Zhao

Jones

Thoreson

et al. 2008

JARO

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Unlike the structural and mechanical role of bone crystals, the inertial mass of otoconia crystals provides a shearing force to stimulate the mechanoreceptors of the utricle and saccule (the gravity receptor organ) under the stimuli of linear motion. It is not clear whether otoconia, composed primarily of CaCO 3 and glycoproteins, go through similar calcification processes as bone. We have recently shown that otoconin-90 (Oc90) regulates the growth of otoconia crystals as osteopontin does bone crystals. Here, we analyzed the role of this non-collagenous bone matrix protein, osteopontin, in otoconia formation and balance function utilizing its knockout mice, whose inner ear phenotype has not been examined. Despite the presence of the protein in wild-type otoconia and vestibular hair cells, morphological, ultrastructural, and protein and calcium composition analyses of osteopontin null otoconia show that the protein is not needed for crystal formation, and no evidence of compensatory protein deposition is found. Employment of a wide spectrum of balance behavioral tests demonstrates that the protein is not critical for balance function either, which is confirmed by the normal function of the gravity receptor organ directly measured with linear vestibular-evoked potentials (VsEPs). When compared with findings on other otoconins, the data manifest a hierarchy of importance of proteins in crystallization and indicate mechanistic similarities and differences between bone and otoconia calcification.

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Section: Introductionmentioning

confidence: 99%

Osteopontin is not Critical for Otoconia Formation or Balance Function

Zhao

Jones

Thoreson

et al. 2008

JARO

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“…Renal tissues of the MRL/lpr mice overexpress osteopontin compared to controls and proximal tubule expression appears to drive macrophage infiltration. Within the kidney, osteopontin may act as a survival signal and is upregulated in many types of renal damage (Ophascharoensuk et al, 1999). Specifically in humans, lupus nephritis is associated with increased osteopontin expression, particularly in crescents (Hudkins et al, 2000;Okada et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus

et al. 2002

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Osteopontin (SPP1) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with systemic lupus erythematosus (SLE). We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human SLE patients. A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with SLE. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of osteopontin.

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“…6 Beside tubular cell EMT induction, MMP-9 is known to be capable of cleaving osteopontin (OPN), 22 a macrophage chemoattractant and macrophages are well known to have a role in renal fibrosis. [23][24][25] However, whether a protection in renal fibrosis was due to a reduction of macrophage infiltration in MMP-9 KO model is unclear. Furthermore, MMPs including MMP-9 has been shown to exhibit an opposing role at different stages of disease progression including renal disease.…”

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confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

132

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A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early-and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early-and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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

Abstract: 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.

Cited by 274 publications

References 35 publications

Osteopontin is not Critical for Otoconia Formation or Balance Function

Osteopontin is not Critical for Otoconia Formation or Balance Function

An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

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