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Articles in PresS, published online ahead of print March 12, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00346.2001
Submitted on November 20, 2001
Accepted on March 6, 2002
1 Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2 Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: paf10{at}pitt.edu.
Resting calcium absorption by cortical thick ascending limbs (CAL) is passive and proceeds through the paracellular pathway. In contrast, parathyroid hormone (PTH) stimulates active, transcellular Ca absorption. The calcium-sensing receptor (CaSR) is expressed on serosal membranes of CALs. In the present study, we tested the hypothesis that activation of the CAL CaSR indirectly inhibits passive Ca transport and directly suppresses PTH-induced cellular calcium absorption. To test this theory, we measured calcium (JCa) and sodium (JNa) absorption by single perfused mouse CALs. Net absorption was measured microfluorimetrically in samples collected from tubules perfused and bathed in symmetric, Hepes-buffered solutions or where luminal sodium was reduced from 150 to 50 mM. We first confirmed that Gd3+ activated the CaSR by measuring intracellular Ca ([Ca]i) in CALs loaded with fura-2. Upon step-wise addition of Gd3+ to the bath, [Ca]i increased, with a half-maximal rise at 30 µM Gd. JCa and transepithelial voltage, Ve, were measured under symmetric Na-containing solutions. PTH increased JCa by 100% and 30 µM Gd3+ inhibited this effect. Ve was unchanged by either PTH or Gd. Likewise, NPS R-467, an organic CaSR agonist, inhibited PTH-stimulated JCa without altering Ve. Neither PTH nor Gd3+ affected JNa. Addition of bumetanide to the luminal perfusate abolished JNa and Ve. These results show that CaSR activation directly inhibited PTH-induced transcellular Ca absorption and that cellular Ca and Na transport can be dissociated. To test the effect of CaSR activation on passive paracellular Ca transport, JCa was measured under asymmetric Na conditions, where passive Ca transport dominates transepithelial absorption. PTH stimulated JCa by 24% and was suppressed by Gd. In this setting, Gd3+ reduced Ve by 32% indicating that CaSR activation inhibited both transcellular and paracellular Ca transport. We conclude that the CaSR regulates both active transcellular and passive paracellular Ca reabsorption but has no effect on Na absorption by CALs.
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