Differential desensitization of Na coupled transporters with chronic parathyroid hormone (PTH) stimulation

Abstract

PTH regulates renal proximal tubule apical (BBM) and basolateral membrane (BLM) transporters including Npt2a, Na+, K+ ATPase (Na‐K), sodium hydrogen exchangers 1 and 3 (NHE1, NHE3). We have shown that the acute inhibitory effect of PTH on proximal tubule Na‐K activity disappears with chronic PTH treatment, but the inhibitory effect on Npt2a activity persists. We hypothesize that chronic PTH results in desensitization of PTH actions on Na but not phosphate transport. To address this hypothesis, we compared the effect of acute and chronic PTH stimulation on expression and function of transport proteins and signaling pathways in Sprague Dawley rat kidney and in OK cells. Treatment with PTH (5 µg/kg) for 6 h decreased Na‐K activity and Na‐K, NHE1, and NHE3 expression in rat BLM, while chronic treatment with PTH (4 days) increased Na‐K‐activity and expression above control levels. BBM Npt2a expression significantly decreased with acute and chronic PTH treatment. PTH did not affect BLM or BBM PTH receptor expression, while BLM expression of NHERF1 significantly increased. Similar findings were seen in OK cells. After chronic PTH, selective stimulation of OK cell BBM with PTH did not stimulate additional PKA and PKC activity, while stimulation of BLM significantly increased PKC activity. BBM or BLM stimulation with 8‐bromo‐cAMP resulted in further PKA activation; stimulation with phorbol myristate acetate resulted in further PKC activation. We conclude that the effects of PTH on Na transport undergo desensitization at a post‐receptor level while the effects of PTH on phosphate transport do not desensitize. The role of differential NHERF1 regulation in modulating PTH receptor‐transporter signaling is unknown. Support from VAMR.