THE RENAL PTH PTHRP RECEPTOR IS DOWN-REGULATED IN RATS WITH CHRONIC-RENAL-FAILURE

Hypocalcemia, hyperphosphatemia, and resistance to the action of PTH a re well characterized features in the setting of advanced chronic rena l 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 t he present study we have examined the effect of advanced CRF in rats o n the renal expression of PTH/PTHrP receptor (PTH-R). CRF was created by a standard two-step operation (5/6 nephrectomy). Four weeks thereaf ter, 19 uremic rats were compared with 23 sham-operated rats. Uremic r ats had higher mean (+/- SD) plasma creatinine levels than control rat s, 164 +/- 107 mum versus 43 +/- 5 mum, respectively. They also had hi gher plasma phosphorus and iPTH levels, 4.70 +/- 1.71 mm versus 2.59 /- 0.37 mm and 561 +/- 336 versus 27 +/- 18 pg/ml, respectively. Mean plasma total calcium and blood ionized calcium were significantly lowe r in uremic than in control rats, 2.13 +/- 0.06 mm versus 2.61 +/- 0. 10 mm and 1.07 +/- 0. 11 versus 1.31 +/- 0.06 mm, respectively. Mean p lasma calcitriol concentration was also significantly lower in uremic than in control rats, 39.8 +/- 14.6 and 80.4 +/- 15.2 pg/ml, respectiv ely. Nine out of the 19 rats were examined for renal PTH-R gene expres sion. We show for the first time that the level of PTH-R mRNA in the k idney of uremic rats was markedly decreased compared with that of norm al rats, the ratio PTH-R mRNA/beta-actin mRNA being 0.47 +/- 0.12 vers us 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 associa ted with a marked reduction in PTH-sensitive adenylyl cyclase activity in crude renal membranes from uremic rats. The values of basal adenyl yl cyclase activity and subsequently after stimulation by forskolin an d 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 t he pathogenesis of the secondary hyperparathyroidism of CRF.