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Renal Sodium Excretion Consequent to Pharmacogenetic Activation of Gq‐DREADD in Principal Cells
Author(s) -
Mironova Elena,
Stockand James
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.862.36
Subject(s) - epithelial sodium channel , endocrinology , medicine , receptor , nephron , excretion , kidney , stimulation , chemistry , biology , sodium , organic chemistry
Stimulation of Gq‐coupled metabotropic P2Y 2 receptors decrease the activity of ENaC in renal principal cells of the distal nephron. The physiological consequences of disrupting P2Y 2 receptor signaling in the P2Y 2 receptor knockout mouse are decreased sodium excretion and increased arterial blood pressure. However, because of the global nature of this knockout model, the quantitative contribution of ENaC and the distal nephron verses that of upstream renal vascular and tubular elements to changes in urinary excretion and arterial blood pressure are obscure. Moreover, it is uncertain whether stimulation of P2Y 2 receptor inhibition of ENaC is sufficient alone to drive renal sodium excretion. Here we test the sufficiency of targeted stimulation of Gq signaling in principal cells of the distal nephron and P2Y 2 receptors to increase renal sodium excretion using a pharmacogenetic approach and selective agonism of the P2Y 2 receptor. Selective stimulation of the P2Y 2 receptor with the ligand, MRS2768, decreased ENaC activity in freshly isolated tubules as assessed with patch clamp electrophysiology; and rapidly increased urinary sodium excretion as assessed in metabolic cages. Similarly, selective agonism with clozapine N‐oxide (CNO) of hM3Dq‐DREADD restrictively expressed in principal cells of the distal nephron decreased ENaC activity with consequent increases in sodium excretion. CNO when applied to control littermates failed to impact ENaC and renal sodium excretion. These studies represent the first use of the pharmacogenetics DREADD technology in the kidney; and demonstrate that selective activation of the P2Y 2 receptor and Gq signaling in principal cells is sufficient to promote renal salt excretion. Support or Funding Information This research was supported by NIH/NIDDK grants R01DK98460, R01DK103758 and American Heart Association grant 17GRNT32920002 to JDS This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .