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The Local and Systemic Inflammatory Transcriptome after Acute Kidney Injury

Dmitry N. Grigoryev^*, Manchang Liu^*, Heitham T. Hassoun, Chris Cheadle^*, Kathleen C. Barnes^* and Hamid Rabb^*

^* Departments of Medicine and Surgery, Johns Hopkins University, Baltimore, Maryland

Correspondence: Dr. Dmitry N. Grigoryev, Division of Allergy and Clinical Immunology, 5501 Hopkins Bayview Circle, JHAAC 3A.62, Baltimore, Maryland, 21224. Phone: 410-550-1557; Fax: 410-550-2130; E-mail: dgrigor1{at}jhmi.edu

Received for publication April 17, 2007. Accepted for publication October 17, 2007.

Studies in humans and animal models have demonstrated that acute kidney injury (AKI) has a significant effect on the function of extrarenal organs. The combination of AKI and lung dysfunction is associated with 80% mortality; the lung, because of its extensive capillary network, is a prime target for AKI-induced effects. The study presented here tested the hypothesis that AKI leads to a vigorous inflammatory response and produces distinct genomic signatures in the kidney and lung. In a murine model of ischemic AKI, prominent global transcriptomic changes and histologic injury in both kidney and lung tissues were identified. These changes were evident at both early (6 h) and late (36 h) timepoints after 60-min bilateral kidney ischemia and were more prominent than similar timepoints after sham surgery or 30 min of ischemia. The inflammatory transcriptome (109 genes) of both organs changed with marked similarity, including the innate immunity genes Cd14, Socs3, Saa3, Lcn2, and Il1r2. Functional genomic analysis of these genes suggested that IL-10 and IL-6 signaling was involved in the distant effects of local inflammation, and this was supported by increased serum levels of IL-10 and IL-6 after ischemia-reperfusion. In summary, this is the first comprehensive analysis of concomitant inflammation-associated transcriptional changes in the kidney and a remote organ during AKI. Functional genomic analysis identified potential mediators that connect local and systemic inflammation, suggesting that this type of analysis may be a useful discovery tool for novel biomarkers and therapeutic drug development.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673