Reduced phosphate transport in the renal proximal tubule cells in cystinosis is due to decreased expression of transporters rather than an energy defect.

Nephropathic cystinosis is an autosomal recessive disorder caused by mutations in the CTNS gene [1], which encodes for a transporter (cystinosin) responsible for cystine efflux from lysosomes. In cystinotic renal proximal tubules (RPTs), the defect in cystinosin function results in reduced reabsorption of solutes by apical Na(+)/solute cotransport systems, including the Na(+)/phosphate (Pi) cotransport system [2]. However the underlying molecular mechanisms are unknown, given the lack of an appropriate cellular model. To obtain such a model system, we have knocked down cystinosin with siRNA in primary RPT cell cultures. An 80% reduction in cystinosin strongly inhibited Na(+) dependent Pi uptake (70%). Although this finding could be explained by a direct effect on transporters as well as by altered energetics (the ATP level dropped by 52%), our results demonstrate a lack of involvement of Na, K-ATPase, and a reduction in the number of NaPi2a transporters.