Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

Abstract

PTH is a critical regulator of serum phosphorus. We have previously shown that PTH decreases proximal tubule NpT2a mRNA expression through post‐transcriptional mechanisms, and that this effect can be reproduced by treatment with 8‐bromo‐cAMP, a PKA activator, but not phorbol myristate acetate, a PKC activator. We hypothesize that PKA is the primary mediator of NpT2a mRNA destabilization by PTH. To determine the contribution of each pathway to the PTH response, opossum kidney (OK) cells were treated with selective protein kinase inhibitors in the presence of PTH, and NpT2a mRNA expression was measured by qRT‐PCR. Pretreatment with 10µM PKC inhibitor peptide (PKCi) followed by 100nM PTH for 6h produced a 43.9% decrease in NpT2a mRNA versus PKCi alone. Pretreatment with 10µM H‐89, a PKA inhibitor, prevented the initial decrease in NpT2a mRNA by PTH but did not prevent the ultimate reduction. 8CPT‐2Me‐cAMP, a selective activator of Epac, failed to produce a decrease in NpT2a mRNA after 6h. We conclude that the initial effect of PTH on NpT2a mRNA is PKA‐dependent, whereas chronic regulation involves both the PKA and PKC pathways. Grant Funding Source: Support for this project is provided by VA to EDL.

Regulation of Hormone-Sensitive Renal Phosphate Transport

“…The results, which confirm the role of the PLC-PKC signaling pathway for long-term phosphate homeostasis, are not due to PTH resistance, per se, because PTH exerted normal regulatory effects on 1,25[OH] 2 D 3 (Guo et al, 2013). The conclusion that chronic regulation of Npt2a involves PKA and PKC pathways is consistent with the finding that both pathways are involved in PTHdependent Npt2a mRNA downregulation (Murray, Khundmiri, Clark, & Lederer, 2014).…”