Increased endothelin-1 expression in the kidney in hypercalcemic rats

Naoki Shiraishi, Kenichiro Kitamura, Yukimasa Kohda, Takefumi Narikiyo, Masataka Adachi, Taku Miyoshi, Kozo Iwashita, Hiroshi Nonoguchi, R. Tyler Miller, Kimio Tomita

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Background. Although hypercalcemia causes diuresis and natriuresis, the molecular mechanisms of these effects are not well established. Recently, the important role of the calcium-sensing receptor (CaR) in hypercalcemia-induced polyuria was reported. Endothelin-1 (ET-1) that is locally produced in the nephron has been suggested to have the natriuretic and/or diuretic effects in the kidney. Therefore, we hypothesized that ET-1 expression could be increased through the activation of CaR in the kidney in hypercalcemia. Methods. Rats were made hypercalcemic by dihydrotachysterol (DHT) treatment. The urinary concentration of ET-1 and the mRNA expression of ET-1 in the kidney were determined. Immunohistochemistry was performed to determine types of the cells that produce ET-1. CaR and ET-1 promoter luciferase constructs were co-expressed in COS-7 cells and the ET-1 promoter activity following the addition of extracellular calcium was measured by the luciferase assay. Results. In hypercalcemic rat, urinary ET-1 excretion was increased by twofold, and ET-1 mRNA expression was increased in the kidney cortex by threefold. In cortical collecting duct (CCD), both principal cells and intercalated cells synthesized ET-1. In cells that express CaR, ET-1 promoter was activated in a dose-dependent manner by extracellular calcium over the range of 0.5 to 3.0 mmol/L. Conclusions. First, activation of CaR increases ET-1 transcription in a dose-dependent manner. Second, hypercalcemia increases ET-1 production in the kidney cortex. These data suggest the possibility that CaR might play an important role in hypercalcemia-induced increase in ET-1 production.

Original languageEnglish (US)
Pages (from-to)845-852
Number of pages8
JournalKidney international
Issue number3
StatePublished - Mar 1 2003


  • Calcium-sensing receptor
  • Endothelin
  • Hypercalcemia
  • Polyuria

ASJC Scopus subject areas

  • Nephrology


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