Abstract for presentation at Australia and New Zealand Society of Nephrology Annual Scientific Conference

Distinct Mechanisms by which JNK1 and MKK3 Signalling Contribute to Streptozotocin-Induced Type 1 Diabetes

  • Dr Kyoichi Fukada, Department of Nephrology, Monash Medical Centre, Australia
  • Dr Greg Tesch, Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Australia
  • Prof Richard Flavell, Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, United States
  • Prof Roger Davis, Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical School, United States
  • Dr David Nikolic-Paterson, Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Australia

    • Diabetes is a major cause of end-stage renal failure. Activation of the JNK and p38 MAPK pathways has been implicated in pancreatic injury. The current study examined whether signaling through individual elements of the JNK or p38 pathways is essential for streptozotocin (STZ)-induced type 1 diabetes. Five daily STZ injections (40mg/kg) were performed in male Jnk1-/-, Jnk2-/-, Mkk3-/- and wild type (WT) C57BL/6J mice. Hyperglycaemia was evident in WT mice within 2 weeks of STZ administration and was associated with b-cell apoptosis, islet leukocyte infiltration, and a loss of insulin producing cells. Jnk2-/- mice showed an increased susceptibility to STZ with significantly elevated blood glucose compared to diabetic WT mice. In contrast, Jnk1-/- and Mkk3-/- mice were protected from STZ-induced hyperglycaemia. Although a significant reduction in b-cell apoptosis was evident in both Jnk1-/- and Mkk3-/- mice, different mechanisms of protection were identified. Islet infiltration by T cells and macrophages was unaltered in Jnk1-/- mice compared to WT, but TNF-a mRNA levels were reduced. Indeed, peritoneal macrophages from Jnk1-/- but not Jnk2-/- mice showed reduced TNF-a secretion in response to cytokine stimulation. In contrast, islet leukocyte infiltration was prevented in Mkk3-/- mice in associated with blockade of MCP-1 mRNA up-regulation. In vitro, cultured islets from Jnk1-/- or Mkk3-/- mice were not protected against STZ or cytokine induced apoptosis compared to WT. In conclusion, MKK3 and JNK1 are critical signaling components in the induction of islet leukocyte infiltration and macrophage activation, respectively, in the development of STZ-induced type 1 diabetes.

    Conference Organiser - ICMS Pty Ltd