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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Mechanism of Diuresis and Natriuresis by Cannabinoids: Evidence for Inhibition of Na+-K+-ATPase in Mouse Kidney Thick Ascending Limb Tubules

Joseph K. Ritter, Ashfaq Ahmad, Shobha Mummalaneni, Zdravka Daneva, Sara K. Dempsey, Ningjun Li, Pin-Lan Li and Vijay Lyall
Journal of Pharmacology and Experimental Therapeutics January 2021, 376 (1) 1-11; DOI: https://doi.org/10.1124/jpet.120.000163
Joseph K. Ritter
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Ashfaq Ahmad
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Shobha Mummalaneni
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Zdravka Daneva
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Sara K. Dempsey
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Ningjun Li
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Pin-Lan Li
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Vijay Lyall
Departments of Pharmacology and Toxicology (J.K.R., A.A., Z.D., S.K.D., N.L., P.-L.L.) and Physiology and Biophysics (S.M., V.L.), Virginia Commonwealth University, Richmond, Virginia
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Abstract

The endocannabinoid, anandamide (AEA), stimulates cannabinoid receptors (CBRs) and is enriched in the kidney, especially the renal medulla. AEA infused into the renal outer medulla of mice stimulates urine flow rate and salt excretion. Here we show that these effects are blocked by the CBR type 1 (CB1) inverse agonist, rimonabant. Immunohistochemical analysis demonstrated the presence of CB1 in thick ascending limb (TAL) tubules. Western immunoblotting demonstrated the presence of CB1 (52 kDa) in the cortex and outer medulla of mouse kidney. The effect of direct [CP55940 (CP) or AEA] or indirect [fatty acyl amide hydrolase (FAAH) inhibitor, PF3845 (PF)] cannabinoidimetics on Na+ transport in isolated mouse TAL tubules was studied using the Na+-sensitive dye, SBFI-AM. Switching from 0 Na+ solution to control Ringer’s solution (CR) rapidly increased TAL cell [Na+]i. Addition of CP to CR produced a further elevation, similar in magnitude to that of ouabain, a Na+-K+-ATPase inhibitor. This [Na+]i-elevating effect of CP was time-dependent, required the presence of Na+ in the bathing solution, and was insensitive to Na+-K+-2Cl− cotransporter inhibition. Addition of PF to CR elevated [Na+]i in FAAH wild-type but not FAAH knockout (KO) TALs, whereas the additions of CP and AEA to PF-treated FAAH KO TALs increased [Na+]i. An interaction between cannabinoidimetics and ouabain (Ou) was observed. Ou produced less increase in [Na+]i after cannabinoidimetic treatment, whereas cannabinoidimetics had less effect after Ou treatment. It is concluded that cannabinoidimetics, including CP and AEA, inhibit Na+ transport in TALs by inhibiting Na+ exit via Na+-K+-ATPase.

SIGNIFICANCE STATEMENT Cannabinoids including endocannabinoids induce renal urine and salt excretion and are proposed to play a physiological role in the regulation of blood pressure. Our data suggest that the mechanism of the cannabinoids involves inhibition of the sodium pump, Na+-K+-ATPase, in thick ascending limb cells and, likely, other proximal and distal tubular segments of the kidney nephron.

Footnotes

    • Received June 11, 2020.
    • Accepted October 6, 2020.
  • This work was supported by National Institutes of Health National Institute of Digestive and Kidney Disorders [Grant DK102539] and National Institute on Drug Abuse [Grants P30DA033934 and T32DA007027].

  • https://doi.org/10.1124/jpet.120.000163.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 1
1 Jan 2021
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Cannabinoids and Sodium Transport in Thick Ascending Limb

Joseph K. Ritter, Ashfaq Ahmad, Shobha Mummalaneni, Zdravka Daneva, Sara K. Dempsey, Ningjun Li, Pin-Lan Li and Vijay Lyall
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 1-11; DOI: https://doi.org/10.1124/jpet.120.000163

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Cannabinoids and Sodium Transport in Thick Ascending Limb

Joseph K. Ritter, Ashfaq Ahmad, Shobha Mummalaneni, Zdravka Daneva, Sara K. Dempsey, Ningjun Li, Pin-Lan Li and Vijay Lyall
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 1-11; DOI: https://doi.org/10.1124/jpet.120.000163
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