pci-32765 and Diabetic-Nephropathies

Topics: Adenine; Aged; Diabetic Nephropathies; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Renal Dialysis; Renal Elimination; Treatment Outcome

Accumulating evidence has shown that macrophages play a vital role in development and pathogenesis of diabetic nephropathy (DN) by secreting inflammatory cytokines. Although Bruton's tyrosine kinases (Btk) is a biologically important molecule implicated in immune regulation, the role of Btk in high glucose (HG)-stimulated inflammatory response in macrophages and the mechanism involved need further investigation. In our study, we used bone marrow-derived macrophages (BMMs) to investigate the involvement of Btk on HG-induced inflammatory cytokines expression and to explore the underlying mechanisms. We found that high glucose induced phosphorylation of Btk, MAPKs and NF-κB, and the expression of downstream inflammation cytokines monocyte chemo-attractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β). Btk inhibitor (PCI-32765) not only down-regulated ERK1/2 phosphorylation and NF-κB activation, but also decreased the secretion of MCP-1, TNF-α and IL-1β in HG-treated BMMs. These results indicate that Btk plays an important role in HG-induced inflammatory cytokines expression and that PCI-32765 may be used as an immunoregulatory agent against hyperglycemia-induced inflammatory response in DN.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Anti-Inflammatory Agents; Bone Marrow Cells; Cells, Cultured; Cytokines; Diabetic Nephropathies; Extracellular Signal-Regulated MAP Kinases; Glucose; Humans; Immunomodulation; Inflammation Mediators; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction