Urinary proteomic analysis of chronic allograft nephropathy

O’Riordan, Edmond; Orlova, Tetiana; Mendelev, Natalia; Patschan, Daniel; Kemp, Robert G.; Chander, Praveen N.; Hu, Ran; Hao, Gang; Gross, Steven S.; Iozzo, Renato V.; Delaney, Veronica; Goligorsky, Michael S.

doi:10.1002/prca.200780137

Cited by 52 publications

(37 citation statements)

References 46 publications

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“…Perlecan proteolysis has been documented in animal models of renal allograft rejection, and direct evidence of microvascular perlecan Growth differentiation factor-9 precursor gdf9 X Fibroblast growth factor-4 fgf4 X Fibroblast growth factor-17 fgf17 X Melanoma-derived growth regulatory protein precursor Mia X Epidermal growth factor Egf X X Abbreviations: HPLC, high performance liquid chromatography; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; SSC-DMSO, serum-free medium conditioned by apoptotic endothelial cells; SSC-ZVAD, serum-free medium conditioned by nonapoptotic edothelial cells. proteolysis in human renal biopsies with evidence of CTV has been reported recently [31,33].…”

Section: Discussionmentioning

confidence: 99%

“…LG3 urinary levels were found to be elevated in renal transplant recipients with CTV, suggesting that LG3 is a novel biomarker of CTV in humans [33,57]. Hence, we evaluated whether factors produced by apoptotic EC, including LG3, could foster a state of resistance to apoptosis conducive to hMSC accumulation at sites of vascular injury.…”

Section: Discussionmentioning

confidence: 99%

“…In turn, proteolysis of basement membrane perlecan leads to the production of an antiapoptotic carboxyl-terminal (C-terminal) fragment active on vascular smooth muscle cells and fibroblasts [29,32]. Intriguingly, this C-terminal perlecan fragment (LG3) was found to be increased in the urine of human renal transplant recipients with chronic rejection, whereas intrarenal microvascular perlecan proteolysis was correlated with chronic renal transplant vasculopathy [33]. Hence, mediators generated by apoptotic endothelial cells (EC) such as LG3 could play a key role in fostering the acquisition of a state of resistance to apoptosis in neointimal cells.…”

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: Discussionmentioning

confidence: 99%

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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“…Furthermore, perlecan has been shown to interact with FGF2 to contribute to fibroblast activation in the development of chronic graft impairment (70). Studies in human renal transplant recipients have confirmed the clinical relevance of perlecan expression in kidney rejection, as higher serum or urinary levels of the perlecan C-terminal fragment associate with acute vascular rejection or advanced chronic allograft nephropathy, respectively (71,72). A recent translational study by Adepu and colleagues also implicated the HS syndecan-1 as important in contributing to graft outcomes in experimental and clinical kidney transplantation (73).…”

Section: Evolving Paradigms For Damps In Sotmentioning

confidence: 92%

Danger signals in regulating the immune response to solid organ transplantation

Todd¹,

Palmer²

2017

Journal of Clinical Investigation

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“…11 In a study from 2004, Nankivell and associates reported that more than 50% of kidney allograft biopsies unveiled attestation of chronic CNI toxicity and after 10 years 100% exhibited this framework of CNI injury. 4 This explains why the small early acute rejection rates have been accomplished using CNI therapy, yet are not accompanied by any long-term benefits.…”

Section: Introductionmentioning

confidence: 99%

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Jayant

Bridson

Sharma³

et al. 2017

Exp Clin Transplant

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Objectives: This review focuses on the current limited evidence of graft function and graft survival in various immunosuppressive regimens involving mammalian target of rapamycin inhibitors with or without calcineurin inhibitors. Materials and Methods: We evaluated the current literature for describing the role of mammalian target of rapamycin inhibitors as an alternative to calcineurin inhibitors by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus databases using medical subject heading terms. Results: Our detailed analyses of all relevant literature showed use of mammalian target of rapamycin inhibitor-based de novo regimens, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimens, and late conversion from a calcineurin inhibitor-based regimen to mammalian target of rapamycin inhibitor-based regimens. Notably, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimen seemed to be a more practical and realistic approach toward immunosuppressive treatment of renal transplant recipients. However, in view of the high rejection rate observed in these studies, it is advisable not to offer these regimens to patients with moderate to high immunologic risk. Conclusions: The present evidences suggest that treatment with mammalian target of rapamycin inhibitors allows early and substantial calcineurin inhibitor minimization. The mammalian target of rapamycin inhibitors everolimus and sirolimus are preferred due to their complementary mechanisms of action and favorable nephrotoxicity profile, which have opened the way for calcineurin inhibitor reduction/withdrawal in the early posttransplant period.

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Urinary proteomic analysis of chronic allograft nephropathy

Cited by 52 publications

References 46 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

Danger signals in regulating the immune response to solid organ transplantation

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