Nephropathic cystinosis, characterized by accumulation of cystine in the 
lysosomes, is caused by mutations in CTNS. The molecular and cellular mechanisms 
underlying proximal tubular dysfunction and progressive renal failure in 
nephropathic cystinosis are largely unclear, and increasing evidence supports 
the notion that cystine accumulation alone is not responsible for the end organ 
injury in cystinosis. We previously identified clusterin as potentially involved 
in nephropathic cystinosis. Here, we studied the expression of clusterin in 
renal proximal tubular epithelial cells obtained from patients with nephropathic 
cystinosis. The cytoprotective secretory form of clusterin, as evaluated by 
Western blot analysis, was low or absent in cystinosis cells compared with 
normal primary cells. Confocal microscopy revealed elevated levels of 
intracellular clusterin in cystinosis cells. Clusterin in cystinosis cells 
localized to the nucleus and cytoplasm and showed a filamentous and punctate 
aggresome-like pattern compared with diffuse cytoplasmic staining in normal 
cells. In kidney biopsy samples from patients with nephropathic cystinosis, 
clusterin protein expression was mainly limited to the proximal tubular cells. 
Furthermore, expression of clusterin overlapped with the expression of apoptotic 
proteins (apoptosis-inducing factor and cleaved caspase-3) and autophagy 
proteins (LC3 II and p62). Silencing of the clusterin gene resulted in a 
significant increase in cell viability and attenuation of apoptosis in 
cystinosis cells. Results of this study identify clusterin as a pivotal factor 
in the cell injury mechanism of nephropathic cystinosis and provide evidence 
linking cellular stress and injury to Fanconi syndrome and progressive renal 
injury in nephropathic cystinosis.