Increased endothelin-1 expression in the kidney in hypercalcemic rats.

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• Hypercalcemia induces polyuria and natriuresis through incompletely understood mechanisms.
• The calcium-sensing receptor (CaR) is implicated in hypercalcemia-induced polyuria.
• Endothelin-1 (ET-1), produced locally in the nephron, may mediate diuretic and natriuretic effects.

Purpose of the Study:

• To investigate the hypothesis that hypercalcemia activates CaR in the kidney, leading to increased ET-1 expression.
• To elucidate the molecular link between CaR activation and ET-1 production in the context of hypercalcemia.

Main Methods:

• Hypercalcemia was induced in rats using dihydrotachysterol (DHT).
• Urinary ET-1 concentration and kidney ET-1 mRNA expression were quantified.
• Immunohistochemistry identified ET-1 producing cells in the kidney.
• CaR and ET-1 promoter activity were assessed in vitro using luciferase assays.

Main Results:

• Hypercalcemic rats exhibited a twofold increase in urinary ET-1 excretion and a threefold increase in kidney cortical ET-1 mRNA.
• ET-1 was synthesized in both principal and intercalated cells of the cortical collecting duct (CCD).
• Extracellular calcium dose-dependently activated the ET-1 promoter in CaR-expressing cells.

Conclusions:

• CaR activation stimulates ET-1 transcription in a dose-dependent manner.
• Hypercalcemia enhances ET-1 production within the kidney cortex.
• These findings suggest CaR plays a significant role in hypercalcemia-induced elevation of renal ET-1 production.