Abstract
Ischemic preconditioning (IPC) is effective in limiting subsequent ischemic acute kidney injury in experimental models. MicroRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. We evaluated the time- and dose-dependence of benefit from IPC in a rat model of functional (bilateral) ischemia–reperfusion injury (IRI). We found optimal protection from subsequent injury following short, repetitive sequences of preconditioning insult. We subsequently used hybridization array and microRNA sequencing to characterize microRNA signatures of protective IPC and of IRI. These approaches identified a profile of microRNA changes consequent on IRI, that were limited by prior IPC. To localize these signals within the kidney, we used laser capture microdissection and RT-qPCR to measure microRNA abundance in nephron segments, pinpointing microRNA changes principally to glomeruli and proximal tubules. Our data describe a unique microRNA signature for IRI in the rat kidney. Pulsatile IPC reduces kidney damage following IRI and diminishes this microRNA signal. We have also identified candidate microRNAs that may act as biomarkers of injury and therapeutic targets in this context.
Highlights
The kidney is a highly metabolically active organ, second only to the brain in terms of oxygen consumption
We selected a model of bilateral ischemia–reperfusion injury (IRI) in the rat, in which there is functional as well as structural renal impairment following injury
Forty-five minutes of bilateral IRI in the rat caused marked histological damage at 48 h when compared with sham controls, exemplified by acute tubular necrosis, endothelial disruption, glomerular changes and tubulointerstitial inflammation
Summary
The kidney is a highly metabolically active organ, second only to the brain in terms of oxygen consumption. Preconditioning of an organ with brief periods of ischemia limits subsequent ischemia-induced necrosis in experimental in vivo m odels[9], but it has proved challenging to translate this into a beneficial t herapy[10]. This lack of translation may in part reflect the difficulty of titrating “dose” of IPC in a heterogenous patient population, and that the mechanisms underlying the protective effect have not been determined. MicroRNA expression may be quantified by multiple techniques developed for nucleic acid analysis, including profiling by hybridization- and microRNA-sequencing-based techniques, existing profiling approaches may introduce significant b ias[22,23,24]. Components of the kidney through use of laser capture microdissection, and related changes in microRNA expression to those seen in previously determined biomarker evaluations in urine following kidney injury
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