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Calcium-sensing receptor regulation of PTH-inhibitable proximal tubule phosphate transport

Departments of ¹Pharmacology and ³Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; and ²Program in Membrane Biology and Renal Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Submitted 15 July 2003 ; accepted in final form 1 September 2003

Inorganic phosphate (P_i) is absorbed by proximal tubules through a cellular pathway that is inhibited by parathyroid hormone (PTH). The calcium-sensing receptor (CaSR) is expressed on apical membranes of proximal tubules. In the present studies, we determined the effect of luminal and/or basolateral PTH on phosphate absorption and tested the hypothesis that CaSR activation blocks PTH-inhibitable phosphate absorption. Single proximal S3 tubules were dissected from the kidneys of mice and studied by the Burg technique. Tubules were bathed with DMEM culture media supplemented with 6% BSA and perfused with an ultrafiltrate prepared from the bathing solution. ³³P and FITC-inulin were added to the luminal perfusate to measure phosphate absorption (J_Pi) and fluid absorption (J_v), respectively. J_Pi averaged 2.9 pmol·min^–1·mm^–1 under control conditions and decreased by 20% upon addition of serosal PTH. PTH had no effect on J_v. Inclusion of PTH in the luminal perfusate reduced J_Pi to 2.1 pmol · min^–1 · mm^–1. Combined addition of PTH to perfusate and bathing solutions reduced J_Pi to 1.5 pmol · min^–1 · mm^–1 without affecting J_v. Indirect immunofluorescence studies revealed abundant PTH receptor (PTH1R) expression on brush-border membranes, with lower amounts on basolateral membranes. CaSRs were localized primarily, but not exclusively, to brush-border membranes. CaSR activation with luminal Gd³⁺ abolished the inhibitory action of PTH on J_Pi. Addition of Gd³⁺ to the serosal bathing solution had no effect on PTH-sensitive J_Pi. Gd³⁺ i.e., PTH-independent J_Pi. Gd³⁺ did not affect basal, had no effect on J_v when added to lumen or bath. Dopamine-inhibitable J_Pi was not affected by Gd³⁺. Experiments with proximal-like opossum kidney cells showed that elevated extracellular Ca²⁺ or NPS R467, a type II calcimimetic, inhibited PTH action on P_i uptake. In conclusion, PTH1Rs are expressed on apical and basolateral membranes of mouse proximal tubules. Stimulating apical or basolateral PTH1R inhibits phosphate absorption. CaSR activation specifically regulates PTH-suppressible phosphate absorption.

kidney; parathyroid hormone; opossum kidney cells; dopamine; parathyroid hormone receptor

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