Activation of the transcription factor c-Jun in acute cellular and antibody-mediated rejection after kidney transplantation

Kobayashi, Akimitsu; Takahashi, Takamune; Horita, Shigeru; Yamamoto, Izumi; Yamamoto, Hiroyasu; Teraoka, Satoshi; Tanabe, Kazunari; Hosoya, Tatsuo; Yamaguchi, Yutaka

doi:10.1016/j.humpath.2010.04.016

« Previous Next »Human Pathology
Volume 41, Issue 12 , Pages 1682-1693, December 2010

Activation of the transcription factor c-Jun in acute cellular and antibody-mediated rejection after kidney transplantation☆

Akimitsu Kobayashi, MD
- Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei, University School of Medicine, Tokyo 105-8471, Japan
- Corresponding author.
Takamune Takahashi, MD, PhD
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Shigeru Horita
- Kidney Center, Tokyo Women's Medical University, Tokyo 162-8666, Japan
Izumi Yamamoto, MD
- Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei, University School of Medicine, Tokyo 105-8471, Japan
Hiroyasu Yamamoto, MD, PhD
- Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei, University School of Medicine, Tokyo 105-8471, Japan
Satoshi Teraoka, MD, PhD
- Department of Surgery, Tokyo Women's Medical University, Tokyo 162-8666, Japan
Kazunari Tanabe, MD, PhD
- Department of Urology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
Tatsuo Hosoya, MD, PhD
- Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei, University School of Medicine, Tokyo 105-8471, Japan
Yutaka Yamaguchi, MD
- Department of Pathology, Kashiwa Hospital, The Jikei University School of Medicine, Chiba 277-8567, Japan

Received 10 February 2010; received in revised form 13 April 2010; accepted 30 April 2010. published online 05 August 2010.

Summary

c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined. We investigated whether c-Jun is activated in acute allograft rejection. c-Jun activation was assessed with immunohistochemistry using phospho-specific c-Jun antibodies in control human renal tissue and renal tissue from patients with acute cellular rejection, acute antibody-mediated rejection, and no rejection in the month after transplantation. In patients with acute cellular rejection, c-Jun activation was observed primarily in infiltrated T cells associated with tubulitis, interstitial cell infiltration, and endarteritis. The number of infiltrated phosphorylated c-Jun–positive cells in the tubules and interstitium was correlated with the Banff classification “t” and “i” scores. In patients with acute antibody-mediated rejection, c-Jun activation was observed in injured endothelial cells as well as in infiltrated cells, including macrophages, in the glomerular and peritubular capillaries. Furthermore, the serum creatinine levels and changes in serum creatinine from the previous year were significantly correlated with the total tubulointerstitial phosphorylated c-Jun–positive score (representing the number of positive nuclei in the tubules, interstitium, and peritubular capillaries). In conclusion, c-Jun was activated in acute antibody-mediated rejection and acute cellular rejection and was associated with reduced graft function. These findings suggest that c-Jun plays a key role in pathological events and may represent a novel therapeutic target in acute renal allograft rejection.

Keywords: c-Jun, Acute allograft rejection, Kidney transplantation, JNK