Boolean Logic Coupled with Overrepresentation Analysis Reveals Activation of the Platelet-derived Growth Factor Receptor Beta Pathway in a Model of Oliguric Acute Kidney Injury; Implications for Transition to Chronic Kidney Disease

Abstract

Acute Kidney Injury (AKI) can occur secondary to insults including sepsis, ischemia and contrast dye administration. A time-sensitive increase in serum creatinine (SCr) or reduction in urine output (UO) has been used to define AKI and stage its severity. Oliguria or significantly reduced UO in AKI or oliguric AKI can have a major impact on outcomes including a transition to chronic kidney disease (CKD). We used Boolean logic coupled with overrepresentation analysis to identify the pathway activation signature associated with oliguric AKI in a published study of rat kidney-ischemia reperfusion. In the reperfused kidney, bulk transcriptomic analysis revealed 1068 differentially expressed genes (DEGs). Those DEGs that correlated with UO and SCr were submitted to gene ontology biological process overexpression analysis. The pathway activation signature associated with oliguric AKI included positive regulation of profibrotic platelet-derived growth factor receptor beta signaling (fold-enrichment >44) driven by src, hip1 and hip1r. Together these findings not only suggest that oliguric AKI may be associated with activation of a pathway leading to fibrosis and CKD but also informs an array of targets to potentially mitigate transition to CKD. HighlightsMechanistic insights should illuminate therapies. A model of rat kidney-ischemia reperfusion injury was queried by correlating kidney transcriptomics with kidney function to identify the pathway activation signature of oliguric AKI. The most striking feature associated with oliguric AKI was positive regulation of platelet-derived growth factor receptor {beta} driven by src, hip1, and hip1r. The pathway activation signature in oliguric AKI informs not only the sequel to injury but also an array of targets to mitigate the potential transition to kidney fibrosis and CKD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=47 SRC="FIGDIR/small/680804v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@121edc1org.highwire.dtl.DTLVardef@80383borg.highwire.dtl.DTLVardef@1ebc25dorg.highwire.dtl.DTLVardef@1258145_HPS_FORMAT_FIGEXP M_FIG C_FIG