Unique transcriptional programs identify subtypes of AKI

Katherine Xu, Paul Rosenstiel, Neal Paragas, Christian Hinze, Xiaobo Gao, Tian Huai Shen, Max Werth, Catherine Forster, Rong Deng, Efrat Bruck, Roger W. Boles, Alexandra Tornato, Tejashree Gopal, Madison Jones, Justin Konig, Jacob Stauber, Vivette D'Agati, Hediye Erdjument-Bromage, Subodh Saggi, Gebhard WagenerKai M. Schmidt-Ott, Nicholas Tatonetti, Paul Tempst, Juan A. Oliver, Paolo Guarnieri, Jonathan Barasch

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to theinjuryof thekidney tubuleandtheepithelial cells thereof (AKI).Yetneither criterionemphasizes theetiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using lasermicrodissection to isolate specific domains of the kidney, followed by RNAsequencing,we found that thousands of genes responded specifically to iAKI or to vAKI, but very fewresponded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potentialbiomarkers of either iAKI or vAKI, but not both.Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function.

Original languageEnglish (US)
Pages (from-to)1729-1740
Number of pages12
JournalJournal of the American Society of Nephrology
Volume28
Issue number6
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Nephrology

Cite this

Xu, K., Rosenstiel, P., Paragas, N., Hinze, C., Gao, X., Shen, T. H., Werth, M., Forster, C., Deng, R., Bruck, E., Boles, R. W., Tornato, A., Gopal, T., Jones, M., Konig, J., Stauber, J., D'Agati, V., Erdjument-Bromage, H., Saggi, S., ... Barasch, J. (2017). Unique transcriptional programs identify subtypes of AKI. Journal of the American Society of Nephrology, 28(6), 1729-1740. https://doi.org/10.1681/ASN.2016090974