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Aims: Diabetic nephropathy is a major consequence of inflammation developing in type 1 diabetes, with interleukin‐8 (IL‐8)‐CXCR1/2 axis playing a key role in kidney disease progression. In this study, we investigated the therapeutic potential of a CXCR1/2 non‐competitive allosteric antagonist (Ladarixin) in preventing high glucose‐mediated injury in human podocytes and epithelial cells differentiated from renal stem/progenitor cells (RSC) cultured as nephrospheres. Materials and Methods: We used human RSCs cultured as nephrospheres through a sphere‐forming functional assay to investigate hyperglycemia‐mediated effects on IL‐8 signalling in human podocytes and tubular epithelial cells. Results: High glucose impairs RSC self‐renewal, induces an increase in IL‐8 transcript expression and protein secretion and induces DNA damage in RSC‐differentiated podocytes, while exerting no effect on RSC‐differentiated epithelial cells. Accordingly, the supernatant from epithelial cells or podocytes cultured in high glucose was able to differentially activate leucocyte‐mediated secretion of pro‐inflammatory cytokines, suggesting that the crosstalk between immune and non‐immune cells may be involved in disease progression in vivo. Conclusions: Treatment with Ladarixin during RSC differentiation prevented high glucose‐mediated effects on podocytes and modulated either podocyte or epithelial cell‐dependent leucocyte secretion of pro‐inflammatory cytokines, suggesting CXCR1/2 antagonists as possible pharmacological approaches for the treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Clear cell Renal Cell Carcinoma (ccRCC) is the most common and metastatic urological cancer. Molecular players of ccRCC progression and metastasis are not completely known. Here, using primary cell cultures from patients' specimens, we found that TGFβ1/Smad signalling is more activated in high versus low grade ccRCC and inversely correlates with Abl2 tyrosine kinase protein expression. TGFβ1 treatment increased ubiquitination and degradation of Abl2 protein in ccRCC cell lines by TGFβ1/Smad pathway activation and reactive oxygen species production. 3D invasion and matrix degradation assays showed that Abl2 promoted TGFβ1‐induced ccRCC cell invasion and maturation of invadopodia, a hallmark of tumour invasion and metastasis. Our findings define Abl2 as a new downstream molecule of TGFβ1 signalling and putative target to counteract advanced ccRCC. [ABSTRACT FROM AUTHOR]

Objective: During hypoxia, hepcidin expression is inhibited to allow iron mobilization to sustain erythropoietic expansion. We analyzed molecular mechanisms underlying hypoxia-induced hepcidin inhibition in an in vivo model of acute hypoxia. Methods: Mice were kept under normal or hypoxic conditions for 6 hours and 15 hours and treated with α-PDGF-BB antibody or PDGF-BB receptor inhibitor. Blood, liver, spleen, and bone marrow were collected to extract RNA and protein or to quantify EPO and PDGF-BB. mRNA and protein levels were assessed by RT-PCR and Western blot. Results: Hepcidin was strongly inhibited at 15 hours, and this downregulation followed erythropoiesis activation and upregulation of several growth factors. PDGF-BB, erythroferrone, GDF15, and TWSG1 were upregulated by hypoxia in the bone marrow, but not in spleen or liver. Inactivation of PDGF-BB or its receptor suppressed the hypoxia-induced hepcidin inhibition. Conclusion: Spleen and liver are not involved in the early stages of hypoxia-induced hepcidin downregulation. Our data support the role of PDGF-BB and probably also of erythroferrone in the recruitment of iron for erythropoiesis in the hypoxia setting. The rapid normalization of all the erythroid factors against persistent hepcidin suppression suggests that other signals are involved that should be clarified in future studies. [ABSTRACT FROM AUTHOR]

The products of the human ARG gene and the human ABL gene characterize the Abelson family of non-receptor tyrosine protein kinases. Both genes are ubiquitously expressed. The interactions of these two similar protein kinases are still not well known, although it has been suggested that they could cooperate, with redundant actions, to provide intracellular signals in the cells. Lymphopenia occurs in mice with homozygous disruption of c-abl, indicating that in certain tissues Arg is unable to substitute c-abl functions. In B and T lymphoid cell lines at different stages of differentiation, we studied, by a reverse transcriptase-competitive polymerase chain reaction and Western blotting, Arg and c-abl in order to evaluate whether the expression pattern of the two genes could give insight as to why they do not exhibit overlapping roles in lymphocytes and whether the product levels of the two genes are related to lymphoid differentiation. The data showed that their expression is differently modified in lymphoid B cell lines. The highest Arg transcript and protein levels are in the mature B cells. [Copyright &y& Elsevier]