Injury and progressive loss of peritubular capillaries in the development of chronic allograft nephropathy

Ishíi, Yasuo; Sawada, Tokihiko; Kubota, Keiichi; Fuchinoue, Syouhei; Teraoka, Satoshi; Shimizu, Akira

doi:10.1111/j.1523-1755.2005.00085.x

Cited by 104 publications

(101 citation statements)

References 41 publications

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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%

“…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]. In most forms of pathologic vascular remodeling, including CTV, neointima formation is characterized by subendothelial accumulation of a smooth muscle actin (aSMA)-positive cells, extracellular matrix (ECM) components, and mononuclear leukocytes [2].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…1,3 Endothelial cell (EC) apoptosis is increasingly recognized as an early pathogenic event in fibrosis. A wide array of fibrogenic conditions, such as systemic sclerosis, 4,5 graftversus-host disease 6,7 and chronic rejection of solid allografts, 8,9 has been associated with increased EC apoptosis. Pathophysiological pathways linking endothelial apoptosis to fibrogenesis are still poorly defined.…”

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confidence: 99%

Caspase-3-mediated secretion of connective tissue growth factor by apoptotic endothelial cells promotes fibrosis

et al. 2009

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Apoptosis of endothelial cells (ECs) is an early pathogenic event in various fibrotic diseases. In this study, we evaluated whether paracrine mediators produced by apoptotic ECs play direct roles in fibrogenesis. C3H mice injected subcutaneously with serumfree medium conditioned by apoptotic ECs (SSC) showed increased skin thickness and heightened protein levels of a-smoothmuscle actin (aSMA), vimentin and collagen I as compared with mice injected with medium conditioned by non-apoptotic ECs. Fibroblasts exposed to SSC in vitro showed cardinal features of myofibroblast differentiation with increased stress fiber formation and expression of aSMA. Caspase-3 silencing in ECs prevented the release of mediators favoring myofibroblast differentiation. To identify the fibrogenic factor(s) released by ECs, the protein contents of media conditioned by either apoptotic or non-apoptotic ECs were compared using SDS-PAGE-liquid chromatography (LC)-tandem mass spectrometry (MS/MS) and two-dimensional LC-MS/MS. Connective tissue growth factor (CTGF) was the only fibrogenic protein found increased in SSC. Pan-caspase inhibition with ZVAD-FMK or caspase-3 silencing in ECs confirmed that CTGF was released downstream of caspase-3 activation. The fibrogenic signaling signatures of SSC and CTGF on fibroblasts in vitro were similarly Pyk2-, Src-family kinases-and PI3K dependent, but TGF-b-independent. CTGF-immunodepleted SSC failed to induce myofibroblast differentiation in vitro and skin fibrosis in vivo. These results identify caspase-3 activation in ECs as a novel inducer of CTGF release and fibrogenesis.

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“…Indeed, clinical biopsy studies have shown an association between loss of tubular structure and function on the one hand and capillary rarefaction on the other. 11,12 Because of their limited replicative capacity, renal ECs are thought to be insufficiently capable to completely repair the injured endothelium of the peritubular capillary plexus after IRI. 13,14 Therefore, current therapeutic strategies to prevent microvascular loss have focused on the prevention of pericyte perturbation to reduce capillary rarefaction.…”

mentioning

confidence: 99%

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

Bijkerk¹,

Solingen²,

Boer³

et al. 2014

Journal of the American Society of Nephrology

107

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Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin 2 /Sca-1 + /cKit + hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin 2 /Sca-1 + /cKit + cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin 2 /Sca-1 + /cKit + cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.

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Injury and progressive loss of peritubular capillaries in the development of chronic allograft nephropathy

Cited by 104 publications

References 41 publications

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

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

Caspase-3-mediated secretion of connective tissue growth factor by apoptotic endothelial cells promotes fibrosis

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

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