Chronic renal failure (CRF) is associated with a high fractional phosphate excretion (FEPi), secondary hyperparathyroidism, and resistance to parathyroid hormone (PTH). This study was undertaken to characterize the role of PTH and dietary Pi in the regulation of PTH/PTH-related peptide receptor (PTHrP-R) mRNA and NaPi-IIa mRNA and protein in CRF. The following groups of rats were studied: (1) sham-operated (control); (2) CRF: 6 weeks after 5/6 nephrectomy (NPX); (3) NPX and parathyroidectomy (NPX + PTX); (4) NPX rats fed a low-Pi diet (NPX + LP); (5) sham-operated rats fed a low-Pi diet (control + LP); (6) sham-operated after PTX (control + PTX). Expression of NaPi-IIa mRNA and PTH/PTHrP-R mRNA was determined in the renal cortex by Northern hybridization. NaPi-IIa protein abundance was determined in cortical brush border membranes by immunoblotting. In NPX rats creatinine clearance decreased to 40 +/- 4%, PTH/PTHrP-R mRNA to 52.1 +/- 2% and NaPi-IIa mRNA to 41.2 +/- 5.5% of control. The PTH/PTHrP-R and NaPi-IIa mRNA in the NPX + PTX and NPX + LP group was similar to that in NPX. NaPi-IIa protein abundance was reduced in NPX compared with control, but was increased dramatically in NPX + PTX and NPX + LP compared to NPX, paralleled by a decrease in FEPi. These findings suggest that the elevated FEPi in CRF is maintained by decreased NaPi-IIa mRNA and NaPi-IIa protein abundance. In contrast, the observed decrease in FEPi with PTX or LP diet in CRF is mediated, at least partly, by increased NaPi-IIa protein abundance with no change in NaPi-IIa mRNA, suggesting post-transcriptional regulation of the NaPi-IIa transporter.