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Capacity for purinergic control of renin promoter via P2Y(11) receptor and cAMP pathways

L van Der Weyden1, D J Adams, B J Morris

  • 1Basic & Clinical Genomics Laboratory, Department of Physiology and Institute for Biomedical Research, The University of Sydney, Sydney, Australia.

Hypertension (Dallas, Tex. : 1979)
|January 11, 2000
PubMed

Insights

Adenosine triphosphate (ATP) stimulates renin secretion via the P2Y11 receptor, activating a cAMP pathway. This finding suggests a role for ATP/P2Y11 in sympathetic renin responses and tissue damage.

Area of Science:

  • Molecular Biology
  • Physiology
  • Pharmacology

Background:

  • Renin secretion is stimulated by adenosine triphosphate (ATP) through purinergic P2Y receptors.
  • ATP, a cotransmitter with norepinephrine, is released during cell damage, potentially explaining de novo renin expression in disease states.
  • The P2Y11 receptor subtype uniquely involves cyclic adenosine monophosphate (cAMP) signaling, a known stimulus for renin production.

Purpose of the Study:

  • To investigate the effect of ATP on human renin (REN) gene promoter activity.
  • To elucidate the specific role of the P2Y11 purinergic receptor in mediating ATP-induced renin gene expression.

Main Methods:

  • Developed a novel Calu-6/P2Y11 cell line stably overexpressing the P2Y11 receptor.
  • Utilized reverse transcriptase-polymerase chain reaction (RT-PCR) to confirm P2Y11 mRNA expression in cell lines and various human tissues.
  • Employed transient transfection with luciferase reporter constructs containing the REN promoter and performed Western blotting to assess protein phosphorylation.

Main Results:

  • ATP treatment of Calu-6/P2Y11 cells significantly increased renin mRNA and protein levels (3-fold).
  • ATP stimulation led to a marked increase in REN promoter-luciferase reporter activity (5.8-fold), consistent with P2Y11 activation.
  • ATP-induced renin promoter activation was abolished by mutation of the cAMP response element (CRE) and correlated with CRE binding protein (CREB) phosphorylation.

Conclusions:

  • The novel P2Y11-overexpressing cell line provides a model for studying ATP-mediated renin regulation.
  • ATP activates renin promoter activity via a cAMP-dependent pathway involving CREB phosphorylation, mediated by the P2Y11 receptor.
  • These findings suggest that ATP/P2Y11 signaling may contribute to sympathetic stimulation of renin and renin responses observed in tissue injury.

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