Mechanisms of Chronic Renal Allograft Rejection. II. Progressive Allograft Glomerulopathy in Miniature Swine

Shimizu, Akira; Yamada, Kazuhiko; Sachs, David H.; Colvin, Robert B.

doi:10.1097/01.lab.0000017370.74529.89

Cited by 38 publications

(41 citation statements)

References 36 publications

(40 reference statements)

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“…For example, the intensity of macrophage infiltration in early biopsies of human renal allografts is predictive of subsequent development of fibrosis (40). In miniature swine, persistence of macrophage infiltration following the resolution of an episode of acute rejection also predicted the ultimate evolution of chronic renal allograft rejection (41). An anti-macrophage regimen (gadolinium) also was able to suppress the development of bronchiolitis obliterans, the manifestation of chronic rejection in lung transplants, in a rat model of heterotopic tracheal transplantation (42).…”

Section: Macrophage Depletion Suppresses Cavmentioning

confidence: 88%

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Kitchens

Chase

Uehara

et al. 2007

American Journal of Transplantation

103

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Section: Macrophage Depletion Suppresses Cavmentioning

confidence: 88%

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Kitchens

Chase

Uehara

et al. 2007

American Journal of Transplantation

103

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“…In various fibrotic diseases, apoptosis of EC is an early event and precedes recruitment of fibroblasts, myofibroblast differentiation, and sustained production of ECM components (8,(12)(13)(14)(15)(16). Chronic accumulation of fibroblasts and myofibroblasts is a hallmark of fibrosis and appears to be due, at least in part, to the development of a state of long term resistance to apoptosis in fibroblasts (2,32,33).…”

Section: Discussionmentioning

confidence: 99%

“…In various fibrotic diseases, increased apoptosis of endothelial cells (EC) has been shown to precede recruitment of fibroblasts (12)(13)(14)(15)(16). Our group showed that apoptosis of EC induces ECM proteolysis, leading to the production of novel cryptic fibrogenic factors (17,18).…”

mentioning

confidence: 89%

Perlecan Proteolysis Induces an α2β1 Integrin- and Src Family Kinase-dependent Anti-apoptotic Pathway in Fibroblasts in the Absence of Focal Adhesion Kinase Activation

Laplante

Raymond

Labelle

et al. 2006

Journal of Biological Chemistry

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Dysregulation of apoptosis in endothelial cells (EC) and fibroblasts contributes to fibrosis. We have shown previously that apoptosis of EC triggers the proteolysis of extracellular matrix components and the release of a C-terminal fragment of perlecan, which in turn inhibits apoptosis of fibroblasts. Here we have defined the receptors and pathways implicated in this anti-apoptotic response in fibroblasts. Neutralizing ␣2␤1 integrin activity in fibroblasts exposed to either medium conditioned by apoptotic EC (SSC) or a recombinant perlecan C-terminal fragment (LG3) prevented resistance to apoptosis and is associated with decreased levels of Akt phosphorylation. Co-incubation of fibroblasts for 24 h with SSC or LG3 in the presence of PP2 (AG1879), a biochemical inhibitor of Src family kinases (SFKs) and focal adhesion kinase, showed a significantly decreased anti-apoptotic response. However, focal adhesion kinase gene silencing with RNA interference did not inhibit the anti-apoptotic response in fibroblasts. Src phosphorylation was increased in fibroblasts exposed to SSC, and transfection of fibroblasts with constitutively active Src mutants induced an anti-apoptotic response that was not further increased by SSC. Also, Src ؊/؊ Fyn ؊/؊ fibroblasts failed to mount an anti-apoptotic response in presence of SSC for 24 h but developed a complete anti-apoptotic response when exposed to SSC for 7 days. These results suggest that extracellular matrix fragments produced by apoptotic EC initiate a state of resistance to apoptosis in fibroblasts via an ␣2␤1 integrin/SFK (Src and Fyn)/phosphatidylinositol 3-kinase (PI3K)-dependent pathway. In the long term, additional SFK members are recruited for sustaining the anti-apoptotic response, which could play crucial roles in abnormal fibrogenic healing.

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“…In chronic rejection, T-cell-dependent and antibody responses target the endothelium, contributing to a sustained increase in endothelial apoptosis [6][7][8][9][10][11][12]55]. In turn, endothelial apoptosis leads to a state of hyperadhesiveness, facilitating the recruitment and emigration of lymphocytes and macrophages [56] but also hMSC [23].…”

Section: Discussionmentioning

confidence: 99%

“…T-cell-dependent and antibody-mediated mechanisms target the allograft endothelium, triggering a cascade of events favoring vascular remodeling and neointima formation [2][3][4]. In animal models of chronic renal, heart and, more recently, lung rejection, increased endothelial apoptosis was shown to correlate with CTV development [5][6][7][8][9][10]. Also, the sustainability of the endothelial apoptotic response within human renal and heart allografts was found to be tightly associated with CTV [11,12].…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor and Perlecan Fragments Produced by Apoptotic Endothelial Cells Co-Ordinately Activate ERK1/2-Dependent Antiapoptotic Pathways in Mesenchymal Stem Cells

et al. 2010

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Mounting evidence indicates that mesenchymal stem cells (MSC) are pivotal to vascular repair and neointima formation in various forms of vascular disease. Yet, the mechanisms that allow MSC to resist apoptosis at sites where other cell types, such as endothelial cells (EC), are dying are not well defined. In the present work, we demonstrate that apoptotic EC actively release paracrine mediators which, in turn, inhibit apoptosis of MSC. Serum-free medium conditioned by apoptotic EC increases extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and inhibits apoptosis (evaluated by Bcl-xL protein levels and poly (ADP-ribose) polymerase cleavage) of human MSC. A C-terminal fragment of perlecan (LG3) released by apoptotic EC is one of the mediators activating this antiapoptotic response in MSC.LG3 interacts with b1-integrins, which triggers downstream ERK1/2 activation in MSC, albeit to a lesser degree than medium conditioned by apoptotic EC. Hence, other mediators released by apoptotic EC are probably required for induction of the full antiapoptotic phenotype in MSC. Adopting a comparative proteomic strategy, we identified epidermal growth factor (EGF) as a novel mediator of the paracrine component of the endothelial apoptotic program.LG3 and EGF cooperate in triggering b1-integrin and EGF receptor-dependent antiapoptotic signals in MSC centering on ERK1/2 activation. The present work, providing novel insights into the mechanisms facilitating the survival of MSC in a hostile environment, identifies EGF and LG3 released by apoptotic EC as central antiapoptotic mediators involved in this paracrine response. STEM CELLS 2010;28:810-820 Disclosure of potential conflicts of interest is found at the end of this article.

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Mechanisms of Chronic Renal Allograft Rejection. II. Progressive Allograft Glomerulopathy in Miniature Swine

Cited by 38 publications

References 36 publications

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Perlecan Proteolysis Induces an α2β1 Integrin- and Src Family Kinase-dependent Anti-apoptotic Pathway in Fibroblasts in the Absence of Focal Adhesion Kinase Activation

Epidermal Growth Factor and Perlecan Fragments Produced by Apoptotic Endothelial Cells Co-Ordinately Activate ERK1/2-Dependent Antiapoptotic Pathways in Mesenchymal Stem Cells

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