RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney

Abstract

Background Acute kidney injury (AKI) is defined as a sudden event of kidney failure or kidney damage within a short period. Ischemia-reperfusion injury (IRI) is a critical factor associated with severe AKI and end-stage kidney disease (ESKD). However, the biological mechanisms underlying ischemia and reperfusion are incompletely understood, owing to the complexity of these pathophysiological processes. We aimed to investigate the key biological pathways individually affected by ischemia and reperfusion at the transcriptome level. Results We analyzed the steady-state gene expression pattern of human kidney tissues from normal (pre-ischemia), ischemia, and reperfusion conditions using RNA-sequencing. Conventional differential expression and self-organizing map (SOM) clustering analyses followed by pathway analysis were performed. Differential expression analysis revealed the metabolic pathways dysregulated in ischemia. Cellular assembly, development and migration, and immune response-related pathways were dysregulated in reperfusion. SOM clustering analysis highlighted the ischemia-mediated significant dysregulation in metabolism, apoptosis, and fibrosis-related pathways, while cell growth, migration, and immune response-related pathways were highly dysregulated by reperfusion after ischemia. The expression of pro-apoptotic genes and death receptors was downregulated during ischemia, indicating the existence of a protective mechanism against ischemic injury. Reperfusion induced alterations in the expression of the genes associated with immune response such as inflammasome and antigen representing genes. Further, the genes related to cell growth and migration, such as AKT, KRAS, and those related to Rho signaling, were downregulated, suggestive of injury responses during reperfusion. Semaphorin 4D and plexin B1 levels were also downregulated. Conclusions We show that specific biological pathways were distinctively involved in ischemia and reperfusion during IRI, indicating that condition-specific therapeutic strategies may be imperative to prevent severe kidney damage after IRI in the clinical setting.

Delayed Contralateral Nephrectomy Halted Post-Ischemic Renal Fibrosis Progression and Inhibited the Ischemia-Induced Fibromir Upregulation in Mice

“…Semaphorin-plexin signalling has already been shown to be dysregulated in IR in mice, impairing the integrity of the slit diaphragm [74,77]. Additionally, an RNA-Seq study demonstrated the downregulation of KRAS and another isoform of plexin (PlxnB1) in the human kidney after IR injury [78]. Despite the upregulated miRNAs in our study, PlxnA2 was not suppressed 10 days after IR, but it was upregulated.…”

Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury

“…Next-generation sequencing (NGS) has been widely used to reveal the potential biomarkers and molecular mechanisms of AKI. In ischemia–reperfusion (I/R) kidney injury, RNA-seq from five pairs of human normal and I/R kidney tissues revealed that apoptosis-, metabolism-, and fibrosis-related pathways were dysregulated in I/R tissues ( Park et al, 2020 ). Another cohort of RNA sequencing data found that apoptosis, migration, oxidation–reduction, and proliferation of macrophages were involved in I/R injury.…”

Targeting Mitochondria and Metabolism in Acute Kidney Injury

“…The emergence of RNA-sequencing (RNAseq) has allowed for transcriptome-wide analyses that identify the biological pathways that are implicated in the pathophysiology of various diseases. Multiple studies have utilized RNAseq to identify novel mechanisms of AKI, including the critical genes involved in kidney disease progression and recovery in the last few years [72][73][74][75][76]. Park et al used RNAseq to identify the gene expression changes that occur in multiple phases of in human AKI, including pre-ischemia, during ischemia, and during reperfusion [74].…”

“…Multiple studies have utilized RNAseq to identify novel mechanisms of AKI, including the critical genes involved in kidney disease progression and recovery in the last few years [72][73][74][75][76]. Park et al used RNAseq to identify the gene expression changes that occur in multiple phases of in human AKI, including pre-ischemia, during ischemia, and during reperfusion [74]. Interestingly, dysregulated metabolism and apoptotic pathways were found in the ischemic phase of injury, while cell growth and innate immune pathways were involved in the reperfusion phase.…”