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Transcriptome-Based Analysis of Molecular Pathways for Clusterin Functions in Kidney Cells
Ghida Dairi1,2, Qiunong Guan1, Mani Roshan-Moniri3
1Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Journal of Cellular Physiology
|May 8, 2016
Summary
Clusterin (CLU) protein promotes kidney cell growth and survival. CLU signaling pathways involve PI3K/AKT, PTEN, VEGF, and ERK/MAPK, with UPR/ER stress activation in hypoxia, revealing CLU's protective kidney role.
Area of Science:
- Molecular Biology
- Cellular Physiology
- Renal Pathophysiology
Background:
- Clusterin (CLU) is a chaperone protein with a known protective role in renal ischemia-reperfusion injury (IRI).
- The precise molecular mechanisms underlying CLU's function in kidney cells remain incompletely understood.
- Investigating CLU-mediated pathways is crucial for understanding its protective effects in the kidney.
Purpose of the Study:
- To elucidate the CLU-mediating molecular pathways in kidney cells.
- To investigate the role of CLU in kidney cell behavior under normoxia and hypoxia.
- To identify key signaling cascades influenced by CLU expression in renal tubular epithelial cells (TECs).
Main Methods:
- Utilized CLU null renal tubular epithelial cells (TECs) engineered to express human CLU (TEC-CLU(hCLU)) or an empty vector (TEC-CLU(-/-)).
- Exposed cells to normoxia or hypoxia (1% O2) and performed transcriptome profiling using microarray analysis.
- Analyzed signaling pathways using Ingenuity Pathway Analysis (IPA) for differentially expressed genes.
Main Results:
- Ectopic CLU expression in CLU null kidney cells promoted cell growth and inhibited migration under normoxia.
- CLU enhanced cell survival under hypoxia, affecting thousands of transcripts.
- CLU-mediated pathways in normoxia involved PI3K/AKT, PTEN, VEGF, and ERK/MAPK signaling, and cell cycle regulation.
- In hypoxia, CLU-enhanced survival was linked to PI3K/AKT, PTEN, VEGF, ERK/MAPK signaling, and crucially, unfolded protein response (UPR)/endoplasmic reticulum (ER) stress activation.
Conclusions:
- CLU functions in kidney cells are primarily mediated by a cascade involving PI3K/AKT, PTEN, VEGF, and ERK/MAPK signaling.
- Activation of UPR/ER stress pathways plays a specific role in CLU-mediated cell protection under hypoxic conditions.
- These findings provide novel insights into the protective mechanisms of CLU in the kidney, particularly during hypoxic stress.
