Altered response of adenylate cyclase to parathyroid hormone during compensatory renal growth

Altered response of adenylate cyclase to parathyroid hormone during compensatory renal growth. The loss of renal mass is associated with functional adaptations in the remaining nephrons to maintain homeostasis. Although parathyroid hormone (PTH) is important in the adaptations to phosphate, the mechanisms are not completely defined. In the present studies we examined the response of the adenylate cyclase system to PTH in renal cortical membranes of rat kidneys ten days after unilateral nephrectomy. The kidneys obtained at the time of the initial nephrectomy were used as controls. Unilateral nephrectomy resulted in contralateral compensatory renal growth, as demonstrated by a 24 ± 4.7% (P < 0.01) increase in weight in the remaining kidney. Glomerular filtration rate (GFR) after unilateral nephrectomy was 62% of the control, while basal fractional phosphate excretion was higher in rats with unilateral nephrectomy (7.7 ± 2.1% vs. 2.9 ± 0.8%, P < 0.05). PTH infusion resulted in a similar increase of fractional phosphate excretion and urinary cAMP in both groups. In the absence of added guanine nucleotides, PTH-dependent adenylate cyclase activity in cortical membranes from kidneys with compensatory growth was decreased as compared to controls (Vmax807.5 ± 62.7 pmol cAMP/mg protein/30min vs. 1,384.8 ± 116.1, respectively, P < 0.01). The apparent affinity for PTH stimulation of adenylate cyclase (Kact) was unchanged. Magnesium-dependent adenylate cyclase activity was also decreased in the membranes from kidneys with compensatory growth. However, the kinetics of adenylate cyclase for the substrates ATP-Mg or ATP-Mn were similar. The addition of Gpp(NH)p resulted in a similar maximal response to PTH in the two groups, indicating an increased response of the enzyme to PTH in the presence of the guanine nucleotide. Cholera toxin-dependent ADP-ribosylation of the stimulatory guanine nucleotide binding protein (Gs) showed a marked decrease in the apparent content of the alpha subunit in membranes from kidneys with compensatory growth compared to controls. On the contrary, pertussis toxin-dependent ADP-ribosylation of the inhibitory guanine nucleotide binding protein (Gi) did not show differences in the content of the alpha subunit in both groups of membranes. Since the transduction of the hormone signal from the receptor is mediated by G proteins, the present studies suggest that during compensatory renal growth a decrease in the alpha subunit of Gs could account for