Received July 8, 2007
Accepted on December 28, 2007

BASIC RESEARCH

IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury

Yael Nechemia-Arbely ^*, Daniel Barkan ^*, Galina Pizov , Anat Shriki ^*, Stefan Rose-John , Eithan Galun ^*, and Jonathan H. Axelrod ^*1

*Goldyne Savad Institute of Gene Therapy and Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel; and Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

¹ To whom correspondence should be addressed. E-mail: axelrod{at}hadassah.org.il.

	Abstract

The response to tissue injury involves the coordination of inflammatory and repair processes. IL-6 expression correlates with the onset and severity of acute kidney injury (AKI), but its contribution to pathogenesis remains unclear. This study established a critical role for IL-6 in both the inflammatory response and the resolution of AKI. IL-6–deficient mice were resistant to HgCl₂-induced AKI compared with wild-type mice. The accumulation of peritubular neutrophils was lower in IL-6–deficient mice than in wild-type mice, and neutrophil depletion before HgCl₂ administration in wild-type mice significantly reduced AKI; these results demonstrate the critical role of IL-6 signaling in the injurious inflammatory process in AKI. Renal IL-6 expression and STAT3 activation in renal tubular epithelial cells significantly increased during the development of injury, suggesting active IL-6 signaling. Although a lack of renal IL-6 receptors (IL-6R) precludes the activation of classical signaling pathways, IL-6 can stimulate target cells together with a soluble form of the IL-6R (sIL-6R) in a process termed trans-signaling. During injury, serum sIL-6R levels increased three-fold, suggesting a possible role for IL-6 trans-signaling in AKI. Stimulation of IL-6 trans-signaling with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI. IL-6/sIL-6R reduced lipid peroxidation after injury, suggesting that its protective effect may be largely mediated through amelioration of oxidative stress. In summary, IL-6 simultaneously promotes an injurious inflammatory response and, through a mechanism of trans-signaling, protects the kidney from further injury.