The renal PTH/PTHrP receptor is down-regulated in rats with chronic renal failure

The renal PTH/PTHrP receptor is down-regulated in rats with chronic renal failure. Hypocalcemia, hyperphosphatemia, and resistance to the action of PTH are well characterized features in the setting of advanced chronic renal failure (CRF). Although the underlying mechanisms are ill-understood, clinical and experimental evidence points to both PTH receptor down-regulation and post-receptor abnormalities in their pathogenesis. In the present study we have examined the effect of advanced CRF in rats on the renal expression of PTH/PTHrP receptor (PTH-R). CRF was created by a standard two-step operation (5/6 nephrectomy). Four weeks thereafter, 19 uremic rats were compared with 23 sham-operated rats. Uremic rats had higher mean (± SD) plasma creatinine levels than control rats, 164 ± 107 µM versus 43 ± 5 µM, respectively. They also had higher plasma phosphorus and iPTH levels, 4.70 ± 1.71mM versus 2.59 ± 0.37mM and 561 ± 336 versus 27 ± 18 pg/ml, respectively. Mean plasma total calcium and blood ionized calcium were significantly lower in uremic than in control rats, 2.13 ± 0.06mM versus 2.61 ± 0.10mM and 1.07 ± 0.11 versus 1.31 ±0.06mM, respectively. Mean plasma calcitriol concentration was also significantly lower in uremic than in control rats, 39.8 ± 14.6 and 80.4 ± 15.2 pg/ml, respectively. Nine out of the 19 rats were examined for renal PTH-R gene expression. We show for the first time that the level of PTH-R mRNA in the kidney of uremic rats was markedly decreased compared with that of normal rats, the ratio PTH-R mRNA/β-actin mRNA being 0.47 ± 0.12 versus 0.99 ± 0.23, respectively, and the ratio PTH-R mRNA/28S being 8.9 ± 4.7 versus 19.6 ± 11.1, respectively. This decrease was associated with a marked reduction in PTH-sensitive adenylyl cyclase activity in crude renal membranes from uremic rats. The values of basal adenylyl cyclase activity and subsequently after stimulation by forskolin and NaF were also significantly reduced in comparison to that of normal rats. These data indicate that rats with severe CRF have reduced renal PTH-R expression, associated with diminished basal and PTH-sensitive adenylyl cyclase activity. These abnormalities could be important in the pathogenesis of the secondary hyperparathyroidism of CRF.