Endothelial Dysfunction in Kidney Transplantation

Cardinal, Héloïse; Dieudé, Mélanie; Hébert, Marie‐Josée

doi:10.3389/fimmu.2018.01130

Cited by 49 publications

(40 citation statements)

References 95 publications

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“…Besides the tubular lesions, it has been shown recently that abnormal microvascular endothelial activation following IR‐associated injury can be an important mechanism involved in pathological angiogenesis, allograft rejection, tissue remodeling, and progressive peritubular capillary rarefaction and graft destruction 8‐15 . For this reason, early detection of endothelial injury/activation should be actively sought in order to better understand the mechanisms for graft dysfunction in the long term and to explore preventive intervention options for improving allograft outcomes.…”

Section: Introductionmentioning

confidence: 99%

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts

Xu‐Dubois

Ahmadpoor

Brochériou

et al. 2020

American Journal of Transplantation

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Acute tubular necrosis (ATN), a frequent histopathological feature in the early post–renal transplant biopsy, affects long‐term graft function. Appropriate markers to identify patients at risk of no or incomplete recovery after delayed graft function are lacking. In this study, we first included 41 renal transplant patients whose biopsy for cause during the first month after transplantation showed ATN lesions. Using partial microvasculature endothelial (fascin, vimentin) and tubular epithelial (vimentin) to mesenchymal transition markers, detected by immunohistochemistry, we found a significant association between partial endothelial to mesenchymal transition and poor graft function recovery (Spearman's rho = −0.55, P = .0005). Transforming growth factor–β1 was strongly expressed in these phenotypic changed endothelial cells. Extent of ATN was also correlated with short‐ and long‐term graft dysfunction. However, the association of extensive ATN with long‐term graft dysfunction (24 months posttransplant) was observed only in patients with partial endothelial to mesenchymal transition marker expression in their grafts (Spearman's rho = −0.64, P = .003), but not in those without. The association of partial endothelial to mesenchymal transition with worse renal graft outcome was confirmed on 34 other early biopsies with ATN from a second transplant center. Our results suggest that endothelial cell activation at the early phase of renal transplantation plays a detrimental role.

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Section: Introductionmentioning

confidence: 99%

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts

Xu‐Dubois

Ahmadpoor

Brochériou

et al. 2020

American Journal of Transplantation

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“…In this regard, a previous study with a rat model of renal transplantation showed that the immune response to collagen IV plays a role in allograft rejection (Joosten et al, 2002). Other studies pointed out a role of EVs released by endothelial cells in promoting inflammation and stimulating the immune response of the host (Cardinal et al, 2018). These findings not only suggest a potential role of circulating EVs in the prediction of transplant rejection but also raise possible therapeutic targets in order to counteract the rejection process.…”

Section: Renal Transplant Rejection and Tolerancementioning

confidence: 84%

Novel Aspects of Extracellular Vesicles in the Regulation of Renal Physiological and Pathophysiological Processes

Rigalli

Barros

Sommers

et al. 2020

Front. Cell Dev. Biol.

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Extracellular vesicles (EV) are nanosized particles released by a large variety of cells. They carry molecules such as proteins, RNA and lipids. While urinary EVs have been longer studied as a source of biomarkers for renal and non-renal disorders, research on EVs as regulatory players of renal physiological and pathological processes has experienced an outbreak recently in the past decade. In general, the microenvironment and (patho)physiological state of the donor cells affect the cargo of the EVs released, which then determines the effect of these EVs once they reach a target cell. For instance, EVs released by renal epithelial cells modulate the expression and function of water and solute transporting proteins in other cells. Also, EVs have been demonstrated to regulate renal organogenesis and blood flow. Furthermore, a dual role of EVs promoting, but also counteracting, disease has also been reported. EVs released by renal tubular cells can reach fibroblasts, monocytes, macrophages, T cells and natural killer cells, thus influencing the pathogenesis and progression of renal disorders like acute kidney injury and fibrosis, nephrolithiasis, renal transplant rejection and renal cancer, among others. On the contrary, EVs may also exert a cytoprotective role upon renal damage and promote recovery of renal function. In the current review, a systematic summary of the key studies from the past 5 years addressing the role of EVs in the modulation of renal physiological and pathophysiological processes is provided, highlighting open questions and discussing the potential of future research.

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“…IRI induces a complex vascular phenotype characterized by a progressive spectrum of functional and structural alterations: vasoconstriction, vascular inflammation, microvascular rarefaction of peritubular capillaries, chronic hypoxia, interstitial fibrosis, and tubular atrophy (126,127). Microvascular lesions appear to be a key driver of fibrosis after IRI, with a predominant effect over tubular ones (128).…”

Section: Endothelial Cellsmentioning

confidence: 99%

“…In this scenario, endothelial cell generate both "classical" apoptotic bodies and smaller exosome-like vesicles; both are overloaded with caspase-3 and can propagate cell death. Additionally, these exosome-like vesicles carry activated 20S proteasome; this complex recruits adaptive immune cells and induces the production of auto-antibodies toward perlecan/LG3, angiotensin-1 receptor, and dsDNA, further aggravating vascular inflammation (46,127,131). Reperfusion has also been associated with the occurrence of a broad range of IgM "natural antibodies, " targeting "neo-epitopes" on ischemic tissues and activating complement (123).…”

Section: Endothelial Cellsmentioning

confidence: 99%

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

et al. 2020

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Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors, and functional microRNAs (miRNAs) that may modulate expression of recipient cell genes. As paracrine factors, neutrophil-and macrophage-derived EVs exert immunosuppressive and immune-stimulating effects on dendritic cells, respectively. Dendritic cell-derived EVs mediate alloantigen spreading and modulate antigen presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation or shed complement inhibitors and prevent cell lysis. Likewise, endothelial-and platelet-derived EVs can exert procoagulant/prothrombotic effects and also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial-and tubular-derived EVs play a key role in ischemia-reperfusion injury (IRI) and during the healing process; additionally, they can trigger rejection by inducing both alloimmune and autoimmune responses. Endothelial EVs have procoagulant/pro-inflammatory effects and can release sequestered self-antigens, generating a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGF-β and miR-21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells (MSCs), have been employed as a therapeutic tool in experimental models of rejection and IRI. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis or by inducing autophagy) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation, and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function (DGF) and acute rejection. In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, IRI, autoimmunity, and alloimmunity and are promising as biomarkers and therapeutic tools in KT.

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Endothelial Dysfunction in Kidney Transplantation

Cited by 49 publications

References 95 publications

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts

Novel Aspects of Extracellular Vesicles in the Regulation of Renal Physiological and Pathophysiological Processes

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

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