Ca2+ signalling in human proximal tubular epithelial cells deficient for cystinosin

- We investigated cellular Ca+2 signalling for the first time in nephropathic cystinosis.
- ATP-induced Ca2+ release was slightly potentiated in cystinotic proximal tubular epithelial cells (PTECs).
- The content of acidic Ca2+ stores in cystinotic PTECs were similar to wild-type PTECs.
- IP3-induced Ca2+ release and ITPR3 gene expression were unaffected in cystinotic PTECs.

Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in the CTNS gene coding for the lysosomal cystine transporter, cystinosin. Recent studies have demonstrated that, apart from cystine accumulation in the lysosomes, cystinosin-deficient cells, especially renal proximal tubular epithelial cells are characterized by abnormal vesicle trafficking and endocytosis, possible lysosomal dysfunction and perturbed intracellular signalling cascades. It is therefore possible that Ca2+ signalling is disturbed in cystinosis, as it has been demonstrated for other disorders associated with lysosomal dysfunction, such as Gaucher, Niemann-Pick type C and Alzheimer's diseases. In this study we investigated ATP-induced, IP3-induced and lysosomal Ca2+ release in human proximal tubular epithelial cells derived from control and cystinotic patients. No major dysregulation of intracellular Ca2+ dynamics was found, although ATP-induced Ca2+ release appeared slightly sensitized in cystinotic cells compared to control cells. Hence, these subtle changes in Ca2+ signals elicited by agonists may contribute to the pathogenesis of the disease.

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