The purpose of this study was to evaluate whether the natriuresis and polyuria seen in parathyroid hormone (PTH)-induced hypercalcemia is associated with dysregulation of renal sodium transporters. Rats were infused subcutaneously with three different doses of human PTH (PTH 1-34; 7.5, 10, and 15µg/kg/d) or vehicle for 48 h using osmotic minipumps. The rats treated with PTH developed significant hypercalcemia (plasma total calcium levels: 2.71 ± 0.03, 2.77 ± 0.02 and 3.42 ± 0.06 mmol/L, respectively, P<0.05 compared with corresponding controls). The rats with severe hypercalcemia induced by high-dose PTH developed decreased GFR, increased urine output, reduced urine osmolality, increased urinary sodium excretion and fractional excretion of sodium. This was associated with downregulation (calculated as fraction of control levels) of whole kidney expression of NaPi-2 (16 ± 6%), NHE3 (42 ± 7%), Na,KATPase (55 ± 2%), and BSC-1 (25 ± 4%). In contrast, an upregulation of the CaR was observed. Rats treated with moderate-dose PTH exhibited unchanged GFR but decreased urine concentration. The whole kidney expression of NHE3 (52 ± 8%) and NaPi-2 (26 ± 5%) was persistently decreased, whereas BSC-1 and Na,K-ATPase protein levels were not altered. CaR expression was also increased. Moreover, rats treated with low-dose PTH showed very mild hypercalcemia but unchanged GFR, normal urinary concentration and unchanged expression of sodium transporters and CaR. In conclusion, the reduced expression of major renal sodium transporters is likely to play a role in the increased urinary sodium excretion and decreased urine concentration in rats with PTH-induced hypercalcemia. Moreover, the increase in the CaR in the TAL may indicate a potential role for the CaR in the inhibition of sodium transport in TAL.