Defining the acute kidney injury and repair transcriptome

Abstract

The mammalian kidney has an intrinsic ability to repair after significant injury. However, this process is inefficient: patients are at high risk for the loss of kidney function in later life. No therapy exists to treat established acute kidney injury (AKI) per se: strategies to promote endogenous repair processes and retard associated fibrosis are a high priority. Whole-organ gene expression profiling has been used to identify repair responses initiated with AKI, and factors that may promote the transition from AKI to chronic kidney disease. Transcriptional profiling has shown molecular markers and potential regulatory pathways of renal repair. Activation of a few key developmental pathways has been reported during repair. Whether these are comparable networks with similar target genes with those in earlier nephrogenesis remains unclear. Altered microRNA profiles, persistent tubular injury responses, and distinct late inflammatory responses highlight continuing kidney pathology. Additional insights into injury and repair processes will be gained by study of the repair transcriptome and cell-specific translatome using high-resolution technologies such as RNA sequencing and translational profiling tailored to specific cellular compartments within the kidney. An enhanced understanding holds promise for both the identification of novel therapeutic targets and biomarker-based evaluation of the damage-repair process.

Keywords: Acute kidney injury; TRAP; cancer; development; miRNA; repair; transcriptome.

Figure 1

TRAP RNA-seq work flow (see ref for full details on approach)

Figure 2

Cell type-specific responses observed through cell type specific TRAP analysis 24 hours post IRI. N: No Surgery; S: Sham Surgery; I: IRI Surgery. The heatmap displays the relative microarray probe intensity for given gene across samples. The representation of data was generated using GenePattern. Six2CRE: labels the nephron; Foxd1CRE: labels the interstitial cells including mesangial and podocytes; Cdh5CRE: labels the vascular endothelium, and Lyz2-CRE: labels the cells of myeloid lineage, notably, monocytes, macrophages, neutrophils, and dendritic cells. See Figure 1 for more details.

Figure 3

Analysis of gene expression changes observed in two studies of unilateral ischemia reperfusion injury (IRI) invoked kidney damage 48 hours, or later, post injury initiation. Genes showing a > than 1.5 fold expression change where compared in studies of Ko et al., (DATE; profiling 3, 10, and 28 days post injury initiation) and Risse et al., (DATE; profiling 2, 5, 7 and 14 days post injury initiation). Genes shared between studies, or unique to each study, are indicated.