Clusterin (CLU) is a chaperone-like
protein and plays a protective role against renal
ischemia-reperfusion injury (IRI); however, the molecular pathways for its functions in the kidney are not fully understood. This study was designed to investigate CLU-mediating pathways in kidney cells by using bioinformatics analysis. CLU null renal tubular epithelial cells (TECs) expressing human CLU
cDNA (TEC-CLU(hCLU) ) or empty vector (TEC-CLU(-/-) ) were exposed to normoxia or
hypoxia (1% O2 ). Transcriptome profiling with a significant twofold change was performed using SurePrint G3 Mouse Gene Expression 8 × 60 K microarray, and the signaling pathways was ranked by using Ingenuity pathway analysis. Here, we showed that compared to CLU null controls, ectopic expression of human CLU in CLU null kidney cells promoted cell growth but inhibited migration in normoxia, and enhanced cell survival in
hypoxia. CLU expression affected expression of 3864 transcripts (1893 up-regulated) in normoxia and 3670 transcripts (1925 up-regulated) in
hypoxia. CLU functions in normoxia were associated mostly with AKT2/PPP2R2B-dependent PI3K/AKT, PTEN,
VEGF, and ERK/MAPK signaling and as well with GSK3B-mediated cell cycle progression. In addition to unfolded protein response (UPR) and/or endoplasmic reticulum (ER) stress, CLU-enhanced cell survival in
hypoxia was also associated with PIK3CD/MAPK1-dependent PI3K/AKT, HIF-α, PTEN,
VEGF, and ERK/MAPK signaling. In conclusion, our data showed that CLU functions in kidney cells were mainly mediated in a cascade manner by PI3K/AKT, PTEN,
VEGF, and ERK/MAPK signaling, and specifically by activation of UPR/ER stress in
hypoxia, providing new insights into the protective role of CLU in the kidney. J. Cell. Physiol. 231: 2628-2638, 2016. © 2016 Wiley Periodicals, Inc.