Role of TPC1 in proximal tubular function

In this collaboration between the team of N. Klugbauer from the Department of Experimental and Clinical Pharmacology and Toxicology and A. Just from the Department of Physiology the role of two-pore channel TPC1 in proximal tubular function was studied. TPC1 is an ion channel expressed in endosomal compartments and thought to be involved in the regulation of intracellular vesicle trafficking.

Confocal immunohistochemistry revealed that TPC1 is highly expressed in the proximal, but not the distal tubule of the kidney, throughout intracellular compartments with subapical accumulation.

To discover the functional role of TPC1 in this location, the excretion of phosphate (as indicator for transport activity of NaPiIIa) as well as urine volume, ammonium, and pH (as indicator for NHE3) were studied in vivo in wildtype (wt) mice and TPC1-knockout (TPC1-ko) littermates, in response to dynamic challenges induced by bolus injection of parathyroid hormone (PTH) or acid–base transitions via consecutive infusion of NaCl, Na2CO3, and NH4Cl. Possible involvement of TPC1 in proximal tubular protein reabsorption was assessed by genotype comparison of urinary protein composition.

It was found that in TPC1-ko mice, the PTH-induced rise in phosphate excretion was prolonged and exaggerated, and its recovery delayed in comparison to wt mice, most prominently around ~75 min after PTH. In the acid–base transition experiment, TPC1-ko showed the same rise in phosphate excretion in response to Na2CO3 as wt mice, but a delayed NH4Cl-induced recovery. Ammonium-excretion decreased with Na2CO3, and increased with NH4Cl, but without differences between genotypes. Confocal microscopic analysis of the distribution of NaPiIIa within the apical brush border of proximal tubular cells in comparison to that of actin 75 min after bolus injection of PTH revealed more apical distribution of NaPiIIa along the microvilli in wt than in TPC1-ko animals. Urinary protein composition was not different between genotypes.

These data indicate, that TPC1 is expressed subapically in the proximal but not the distal tubule and is involved in the rapid upregulation of phosphate reabsorption following previous downregulation, presumably via signaling apical redistribution of remnant NaPiIIa along the microvilli. In contrast, regulation of NHE3 and proximal tubular protein reabsorption do not seem to involve TPC1.

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Just A., Mallmann R., Grossmann S., Sleman F., Klugbauer N.
Two-pore channel protein TPC1 is a determining factor for the adaptation of proximal tubular phosphate handling.
Acta Physiol (Oxf.) 4: e13914, 2023    (doi: 10.1111/apha.13914)

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