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Impaired parathyroid hormone receptor-adenylate cyclase system in the postobstructed canine kidney
Abstract:
The present studies examine the initial events in the action of PTH, namely receptor binding and adenylate cyclase activation in the postobstructed canine kidney. Both kidneys were removed from five mongrel dogs 2 h after relief of unilateral ureteral obstruction (UUO) of 42 h duration. Basolateral membranes (BLM) were prepared from both the UUO and contralateral (control) kidneys. Maximal activation of adenylate cyclase by PTH was 35% lower (P less than 0.01) in BLM from UUO than control kidneys (3869 +/- 200 vs. 5978 +/- 425 pmol cAMP/mg protein X 30 min). The concentration of PTH required for half-maximal activation of the enzyme was unchanged. Addition of 1 mM GTP failed to correct the decreased enzyme activity in response to PTH of BLM from kidneys with UUO. NaF activation, a measure of interaction of the nucleotide regulatory component (G/F) with the catalytic unit of the adenylate cyclase was similar in BLM from UUO and control kidneys. Similarly, activation of the catalytic unit of the enzyme by Mn2+ was not different. Specific binding of [125I]Nle8, Nle8, Tyr34-bovine PTH NH2 was markedly reduced (P less than 0.01) in BLM from UUO vs. control (6.37 +/- 1.20 vs. 2.43 +/- 0.09 fmole bound/microgram protein). There was no change in hormone affinity for the binding site. These data indicate that there is decreased activation of adenylate cyclase by PTH as a consequence of apparent loss of receptors for the hormone in the BLMs of renal tubular cells of postobstructed kidneys. These abnormalities may play a role in the abnormal regulation of phosphorus excretion after ureteral obstruction.
Insights
Post-ureteral obstruction, kidneys show reduced parathyroid hormone (PTH) action due to fewer hormone receptors. This impacts adenylate cyclase activation and may affect phosphorus regulation.
Area of Science:
- Nephrology
- Endocrinology
- Cellular Biology
Background:
- Unilateral ureteral obstruction (UUO) is a common condition affecting kidney function.
- Parathyroid hormone (PTH) plays a crucial role in renal physiology, including phosphorus regulation.
- Understanding initial PTH action events is key to deciphering post-obstruction kidney dysfunction.
Purpose of the Study:
- To investigate the initial events of PTH action, specifically receptor binding and adenylate cyclase activation, in post-obstructed canine kidneys.
- To determine if UUO affects the ability of PTH to activate adenylate cyclase.
- To explore the potential role of these molecular changes in abnormal phosphorus excretion.
Main Methods:
- Basolateral membranes (BLM) were isolated from kidneys of dogs subjected to 42-hour UUO and contralateral controls.
- Adenylate cyclase activity was measured by PTH and NaF stimulation.
- Specific binding of radiolabeled PTH ([125I]bPTH) to BLM was quantified.
Main Results:
- Maximal adenylate cyclase activation by PTH was significantly reduced (35%) in BLM from UUO kidneys compared to controls.
- Specific binding of [125I]bPTH was markedly reduced in BLM from UUO kidneys, indicating a loss of receptors.
- PTH affinity for its binding site and NaF-stimulated adenylate cyclase activity remained unchanged, suggesting receptor-related defects.
Conclusions:
- Post-obstructed kidneys exhibit decreased PTH-stimulated adenylate cyclase activity.
- This functional deficit is primarily attributed to a significant reduction in PTH receptors on renal tubular cell basolateral membranes.
- These receptor abnormalities may contribute to the impaired phosphorus excretion observed after ureteral obstruction.