Coagulation and Fibrinolysis in Kidney Graft Rejection

Coagulation system is currently considered an integrated part of innate immunity. Clotting activation in response to bacterial surface along with complement cascade priming represents the first line of defense against pathogens. In the last three decades, we learned that several coagulation factors, including factor II or thrombin and factor X, can interact with specific cell surface receptors activated by an unusual proteolytic mechanism and belonging to a novel class of G-protein-coupled receptors known as protease-activated receptors (PARs). PARs are expressed by a variety of cells, including monocytes, dendritic cells, and endothelial cells and may play a key role in the modulation of innate immunity and in the regulation of its interaction with the adaptive branch of the immune system. Also, the fibrinolytic system, in which activation is controlled by coagulation, can interact with innate immunity, and it is a key modulator of extracellular matrix deposition eventually leading to scarring and fibrosis. In the setting of kidney transplantation, coagulation and fibrinolytic systems have been shown to play key roles in the ischemia/reperfusion injury featuring delayed graft function and in the pathogenesis of tissue damage following acute and chronic rejection. In the present review, we aim to describe the mechanisms leading to coagulation and fibrinolysis activation in this setting and their interaction with the priming of the innate immune response and their role in kidney graft rejection

The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation

Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response. In addition to their role in anti-viral and anti-tumor defense, they also regulate several aspects of the allo-immune response in kidney transplant recipients. Growing evidence suggests a key role of NK cells in the pathogenesis of immune-mediated graft damage in kidney transplantation. Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss. Moreover, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. Finally, activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection. In this review, we will describe how these cells can influence the innate and the adaptive immune response in kidney transplantation and how immunosuppression can modulate NK behavior

The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: an updated review

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available

Evaluation of two groups of quinoa (Chenopodium quinoa Willd.) accessions with different seed colours for adaptation to the Mediterranean environment

Agronomic and seed-quality traits in 17 quinoa (Chenopodium quinoa Willd.) accessions grouped according to seed colour (i.e. ochre and yellow) were investigated and compared with the white commercial cultivar Regalona-Baer. These accessions were previously selected from a range of accessions of diverse origin and seed colour for their potential value in a breeding program for cultivars adapted to the southern Italian environment. Field trials were conducted over 2 years in Foggia, southern Italy. The aim was to identify elite genotypes suited to the Mediterranean Basin in terms of high yields and seed quality, by using principal component analysis (PCA) and hierarchical cluster analysis. The genotype and year effects were statistically significant for most parameters investigated, whereas the genotype × year interaction was significant only for seed quality. There were significant differences between the two seed-colour groups for most of the investigated traits, but not for total dry weight, days to flowering, and soluble and insoluble fibre. The major difference between the accessions and cv. Regalona-Baer was lower seed yield for the ochre seed group (30% lower, on average); this was associated with increased plant height (13% higher, on average), greater number of days to maturity (+6 days, on average) and shorter panicle length (21% shorter, on average). These results were observed for both growing seasons. The seed yield of the yellow seed group was similar to Regalona-Baer. Focusing on individual accessions, PCA indicated that accessions Q12, Q18 and Q26 were similar to Regalona-Baer for seed yield, 1000-seed weight, seed area and seed perimeter, and accession Q4 had the highest protein and kaempferol contents for both years. Seed area and perimeter, harvest index, and 1000-seed weight showed positive associations with seed yield, whereas days to flowering, days to maturity and quality traits were negatively correlated with seed yield for both years. Cluster analysis carried out on all of the agronomic and seed-quality traits did not show clear clustering of the accessions based on seed colour alone. The results of this study confirm that both the ochre and yellow quinoa seed groups included elite accessions that can be used directly in future selection programs for the development of high-yielding varieties well adapted to the Mediterranean environment

On-line hemodiafiltration modulates atherosclerosis signaling in peripheral lymphomonocytes of hemodialysis patients

Hemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis

BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation

Adult renal progenitor cells (ARPCs) isolated from human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling and regeneration processes in several tissues. Aim of the study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidney and it was up-regulated in vivo after delayed graft function (DGF) of renal transplant, condition of AKI. ARPCs expressed BMP-Receptors suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced ROS production, NADPH oxidase activity and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at tubular level after DGF. BMP-2 incubation induced α-SMA, collagen-I and fibronectin protein expression in ARPCs. Moreover, α-SMA co-localized with CD133 in vivo after DGF. The oxidative stimulus (H(2)O(2)) induced α-SMA expression in ARPCs, while the anti-oxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that: a) ARPCs express BMP-2; b) this expression is increased in a model of AKI; c) BMP-2 may induce the commitment of ARPCs towards a myofibroblastic phenotype in vitro and in vivo; d) this pro-fibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage

IgE-Mediated Immune Response and Antibody-Mediated Rejection

Active antibody-mediated rejection is the main cause of kidney transplant loss, sharing with SLE the alloimmune response and the systemic activation of the IFN-α pathway. IgE-mediated immune response plays a key role in the development of SLE nephritis and is associated with IFN-α secretion. The aim of our study was to investigate IgE-mediated immune response in antibody-mediated rejection