MicroRNA Expression Data Reveals a Signature of Kidney Damage following Ischemia Reperfusion Injury

Michael D Shapiro,Jonathan G Godwin,Xupeng Ge,Jeff Latz,John Iacomini,Stefan G Tullius,Jessamyn Bagley,Tobias Eckle

doi:10.1371/journal.pone.0023011

Michael D Shapiro, Jonathan G Godwin + Show 6 more

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https://doi.org/10.1371/journal.pone.0023011

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Abstract

Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury, a common problem worldwide associated with significant morbidity and mortality. We have recently examined the role of microRNAs (miRs) in renal IRI using expression profiling. Here we conducted mathematical analyses to determine if differential expression of miRs can be used to define a biomarker of renal IRI. Principal component analysis (PCA) was combined with spherical geometry to determine whether samples that underwent renal injury as a result of IRI can be distinguished from controls based on alterations in miR expression using our data set consisting of time series measuring 571 miRs. Using PCA, we examined whether changes in miR expression in the kidney following IRI have a distinct direction when compared to controls based on the trajectory of the first three principal components (PCs) for our time series. We then used Monte Carlo methods and spherical geometry to assess the statistical significance of these directions. We hypothesized that if IRI and control samples exhibit distinct directions, then miR expression can be used as a biomarker of injury. Our data reveal that the pattern of miR expression in the kidney following IRI has a distinct direction based on the trajectory of the first three PCs and can be distinguished from changes observed in sham controls. Analyses of samples from immunodeficient mice indicated that the changes in miR expression observed following IRI were lymphocyte independent, and therefore represent a kidney intrinsic response to injury. Together, these data strongly support the notion that IRI results in distinct changes in miR expression that can be used as a biomarker of injury.

Highlights

Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury [1,2,3], that results in tubulointerstitial inflammation, cell death and a poorly understood repair process [4,5,6]
principal component analysis (PCA) of miR expression following unilateral warm IRI To examine the possibility that changes in miR expression could be used as a biomarker for IRI, we observed changes in miR expression in C57BL/6 on days 1, 3, 5, 7, 14, 21 and 30 after warm ischemia (IRI) or sham surgery [14]. miR expression in naıve kidneys was used as a day 0 data point
This suggests that the overall changes in miR expression we observed are due to a single process of response to injury

Summary

Introduction

Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury [1,2,3], that results in tubulointerstitial inflammation, cell death and a poorly understood repair process [4,5,6]. Given the emerging role of miRs in the control of various physiological processes, we hypothesized that miRs might play a critical role in the regulation of responses to renal IRI. To test this hypothesis we performed miR expression profiling on RNA isolated from the kidneys of mice that underwent unilateral warm ischemia and sham controls [14]. We determined that IRI leads to lymphocyte independent alterations in miR expression profiles, leading us to hypothesize that changes in miR expression could be used as a biomarker of renal injury resulting from ischemia and subsequent reperfusion. We used spherical geometry to determine whether differences observed in miR expression between groups are significant

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