BACKGROUND: Ischemia-reperfusion injury (IRI) has a significate impact on both short and long-term transplant outcomes, and is a major cause of delayed graft function in kidney transplants. Clusterin (CLU) is a chaperone-like protein with cytoprotective activities against IRI in the kidneys. However, the molecular mechanisms by which CLU protects the kidney have not been well defined. This study was designed to use bioinformatics analysis of transcriptome database to reveal the CLU-activated cellular pathways in the kidneys following IRI.

METHODS AND MATERIALS: IRI in the kidneys of mice was induced by clamping the renal artery at 32°C of body temperature for 45 minute. The transcriptome databases were established by using gene expression microarray set containing 60000 probes (Agilent Technology). The statistical analysis between animal groups was performed by using the Gene Spring program. The biological functions and the signaling pathways were interpreted by using the Ingenuity pathways analysis program.

RESULTS: Here, we showed that CLU-expressing kidneys in wild type (WT) mice were more resistant to IRI than CLU null kidneys in CLU knockout (KO) mice. As compared to the contralateral kidneys, the expression of a large number of transcripts was significantly affected in the kidneys with IRI, and more transcripts were manipulated in ischemic WT kidneys (∼ 1,400 transcripts) than CLU KO counterparts (∼ 900 transcripts). Using the transcriptome of ischemic CLU null kidneys as a background control, it was found that in ischemic WT kidneys 272 Transcripts were up-regulated, while 477 transcripts were down-regulated. Functional pathway analysis suggested that the most manipulated biological processes by these transcripts in the ischemic WT kidneys were related to the pathways for cell survival/proliferation (46%), followed by the signal transduction (20%), olfaction (10%) and signaling of cells (5%). In addition, the most important overrepresented CLU-dependent pathways were Erk1/2, Egr1, JAK/STAT and Gcpr.

CONCLUSION: These data suggest that CLU may regulate the expression of genes mostly related to cell survival/proliferation, cell cycle, signal transduction, olfaction, and signaling of cells. Further functional mapping of these manipulations are required.

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