Two-pore channel protein TPC1 is a determining factor for the adaptation of proximal tubular phosphate handling

AimTwo-pore channels (TPCs) constitute a small family of cation channels expressed in endo-lysosomal compartments. TPCs have been characterized as critical elements controlling Ca2+-mediated vesicular membrane fusion and thereby regulating endo-lysosomal vesicle trafficking. Exo- and endocytotic trafficking and lysosomal degradation are major mechanisms of adaption of epithelial transport. A prime example of highly regulated epithelial transport is the tubular system of the kidney. We therefore studied the localization of TPC protein 1 (TPC1) in the kidney and its functional role in the dynamic regulation of tubular transport. MethodsImmunohistochemistry in combination with tubular markers were used to investigate TPC1 expression in proximal and distal tubules. The excretion of phosphate and ammonium, as well as urine volume and pH were studied in vivo, in response to dynamic challenges induced by bolus injection of parathyroid hormone or acid-base transitions via consecutive infusion of NaCl, Na2CO3, and NH4Cl. ResultsIn TPC1-deficient mice, the PTH-induced rise in phosphate excretion was prolonged and exaggerated, and its recovery delayed in comparison with wildtype littermates. In the acid-base transition experiment, TPC1-deficient mice showed an identical rise in phosphate excretion in response to Na2CO3 compared with wildtypes, but a delayed NH4Cl-induced recovery. Ammonium-excretion decreased with Na2CO3, and increased with NH4Cl, but without differences between genotypes. ConclusionsWe conclude that TPC1 is expressed subapically in the proximal but not distal tubule and plays an important role in the dynamic adaptation of proximal tubular phosphate reabsorption towards enhanced, but not reduced absorption.

Automated summary

Two-pore channels (TPCs) are a type of cation channels found in endo-lysosomal compartments. They are important for regulating Ca2+-mediated vesicular membrane fusion and endo-lysosomal vesicle trafficking. This study investigated the localization of TPC1 in the kidney and its role in the dynamic regulation of tubular transport.