Maladaptive role of IL-6 in ischemic acute renal failure

Mariusz L. Kielar, Reji John, Michael Bennett, James A. Richardson, John M. Shelton, Liying Chen, D. Rohan Jeyarajah, Xin J. Zhou, Hui Zhou, Brett Chiquett, Glenn T. Nagami, Christopher Y. Lu

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166 Scopus citations

Abstract

The role of IL-6 was investigated in murine ischemic acute renal failure. The renal pedicles were clamped for 17 min, and the mice were studied at various times after reperfusion. We found that serum IL-6 increased after murine ischemic renal injury. This increase was associated with increased IL-6 mRNA in the ischemic kidney but not in the contralateral kidney or the liver. Maximal IL-6 production occurred at 4 to 8 h and decreased to baseline by 24 h. Reperfusion of the kidney was required for IL-6 production. In situ hybridization and immunohistochemistry showed that macrophages infiltrated areas adjacent to the vascular bundles in the outer medulla within hours of reperfusion and showed that these macrophages produced IL-6 mRNA. For understanding how macrophages were stimulated to produce IL-6, an in vitro model in which S3 proximal tubular cells were injured by reactive oxygen species was set up. These injured cells released molecules that activated macrophages to produce IL-6 in vitro. IL-6 that was produced in response to renal ischemia was maladaptive because transgenic knockout of IL-6 ameliorated renal injury as measured by serum creatinine and histology. IL-6 transgenic knockout mice were lethally irradiated, and their bone marrow was reconstituted with wild-type IL-6 cells. Such bone marrow transfers abolished the protective effects of transgenic IL-6 knockout. It is concluded that macrophages infiltrate the area of the vascular bundles of the outer medulla, these macrophages produce IL-6, and this IL-6 exacerbates ischemic murine acute renal failure.

Original languageEnglish (US)
Pages (from-to)3315-3325
Number of pages11
JournalJournal of the American Society of Nephrology
Volume16
Issue number11
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Nephrology

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    Kielar, M. L., John, R., Bennett, M., Richardson, J. A., Shelton, J. M., Chen, L., Jeyarajah, D. R., Zhou, X. J., Zhou, H., Chiquett, B., Nagami, G. T., & Lu, C. Y. (2005). Maladaptive role of IL-6 in ischemic acute renal failure. Journal of the American Society of Nephrology, 16(11), 3315-3325. https://doi.org/10.1681/ASN.2003090757