Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability

Abstract

The acute inhibitory effects of parathyroid hormone (PTH) on proximal tubule Na(+)-K(+)-ATPase (Na-K) and sodium-dependent phosphate (NaPi) transport have been extensively studied, while little is known about the chronic effects of PTH. Patients with primary hyperparathyroidism, a condition characterized by chronic elevations in PTH, exhibit persistent hypophosphatemia but not significant evidence of salt wasting. We postulate that chronic PTH stimulation results in differential desensitization of PTH responses. To address this hypothesis, we compared the effects of chronic PTH stimulation on Na-P(i) cotransporter (Npt2a) expression and Na-K activity and expression in Sprague Dawley rats, transgenic mice featuring parathyroid-specific cyclin D1 overexpression (PTH-D1), and proximal tubule cell culture models. We demonstrated a progressive decrease in brush-border membrane (BBM) expression of Npt2a from rats treated with PTH for 6 h or 4 days, while Na-K expression and activity in the basolateral membranes (BLM) exhibited an initial decrease followed by recovery to control levels by 4 days. Npt2a protein expression in PTH-D1 mice was decreased relative to control animals, whereas levels of Na-K, NHERF-1, and PTH receptor remained unchanged. In PTH-D1 mice, NpT2a mRNA expression was reduced by 50% relative to control mice. In opossum kidney proximal tubule cells, PTH decreased Npt2a mRNA levels. Both actinomycin D and cycloheximide treatment prevented the PTH-mediated decrease in Npt2a mRNA, suggesting that the PTH response requires transcription and translation. These findings suggest that responses to chronic PTH exposure are selectively regulated at a posttranscriptional level. The persistence of the phosphaturic response to PTH occurs through posttranscriptional mechanisms.

Regulation of serum phosphate

“…; Murray et al . ). Patients with primary hyperparathyroidism also have elevated FGF23 which would enhance the phosphaturia (Kawata et al .…”

Another Tool in the Fight Against Phosphate Toxicity: Where Will It Fit and What Does It Tell Us about Phosphate Homeostasis?

“…Studies in a model of endogenous hyperparathyroidism demonstrate persistent presence of Npt2a even with significantly elevated PTH levels. 3 Npt2a-I increased urinary Na, Cl, and calcium but had no effect on urine K or pH, consistent with a predominantly proximal tubule effect. The natriuresis occurred without changes in the expression of NHE3, the major proximal tubule sodium transporter, suggesting that the natriuresis is due to Npt2a inhibition only.…”

“…For over a decade, 1,2 approximately 80% of patients with ESKD initiated hemodialysis (HD) with a central venous catheter, despite recommendations to use an arteriovenous fistula (AVF), the preferred vascular access for HD. 3,4 In this issue of JASN, Lee et al 5 examine the AVF outcomes of a representative incident elderly HD population of patients who underwent AVF creation within 6 months of HD initiation (76.9% without prior arteriovenous access surgery) and whose AVFs were used successfully for dialysis with or without assisted maturation within 6 months of AVF creation.…”

Protein-DNA Interactions at the Opossum Npt2a Promoter are Dependent upon NHERF-1

“…The OK and OK-H cells were maintained in culture as previously described [14,15]. The OK proximal tubule cell line is derived from Virginia opossum [16], while OK-H cells are a stable clonal subline that lacks NHERF-1 expression [17][18][19].…”