Abstract: FR-PO1007

Insuline Resistance Promoting the Progression of Chronic Renal Allograft Dysfunction via the ERK1/2-GSK3β-NF-κB Signaling Pathway

Session Information

Category: Transplantation

  • 1701 Transplantation: Basic and Experimental

Authors

  • Zhou, Qin, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
  • Zhao, Zhihong, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
  • Zou, Hequn, The 3rd Affiliated Hospital of Southern Medical University, Guangzhou, China
Background

Several studies had reported that insuline resistance (IR) was an important nonimmunological risk factors for chronic renal allograft dysfunction (CRAD). However, the pathogenesis of IR-mediated CRAD is still unclear. The aim of this study is to investigate the effect of rosiglitazone on ERK1/2-GSK3β-NF-κB signaling pathway in renal transplantation rats with insulin resistance.

Methods

The rats in CRAD group received classical orthotopic F344-Lewis kidney transplantation and then fed with normal diet. The rats in CRAD+IR group administrated with high fat diet for 8 weeks after kidney transplantation. The rats in CRAD+IR+ERK1/2 Inhibitor group and those in CRAD+IR+GSK-3β Inhibitor group were respectively treated with rosiglitazone (ERK1/2 inhibitor, 5mg/kg/d, gavage) and TDZD8 (GSK-3β inhibitor, 1mg/kg/week, tail vein injection) based on above CRAD+IR model. The controls were F344 and Lewis uninephrectomized rats fed with normal diet. Renal tissue was stained with HE and PAS. The expression of ERK1/2-GSK3β-NF-κB signaling proteins and its downstream inflammation factors were evaluated by means of immunohistochemical and western blot assays.

Results

(1) Function and histology: Compared with CRAD group, serum creatinine and 24-hour urinary protein output were significantly increased in CRAD+IR group. Compared with CRAD+IR group, the above indexes were significantly decreased and the infiltration of inflammation cell in transplanted kidney was significantly alleviated in CRAD+IR+ERK1/2 Inhibitor group. (2) Signaling pathway: Compared with CRAD group, the expression of P-ERK1/2, P-GSK3β and P-NF-κB P65 were significantly increased in CRAD+IR group, and the expression of the downstream inflammation proteins MCP-1 and ICAM-1 were increased in CRAD+IR group; Compared with CRAD+IR group, the expression of P-ERK1/2, P-GSK3β, P-NFκB P65,MCP-1 and ICAM-1 were significantly down-regulated in CRAD+IR+ERK1/2 Inhibitor group. The expression of P-NFκB,MCP-1 and ICAM-1 were inhibited by GSK-3β inhibitor.

Conclusion

It is shown that IR promoted CRAD in our rat model and ERK1/2 inhibitor and GSK-3β inhibitor improved the infiltration of inflammation cells in renal allograft tissue at the early stage of CRAD promoted by IR.ERK1/2-GSK3β-NF-κB signaling pathway participant in the pathogenesis of the early stage of CRAD promoted by IR.

Funding

  • Government Support - Non-U.S.