Cannabinoid receptor type 1 activation causes a water diuresis by inducing an acute central diabetes insipidus in mice

Am J Physiol Renal Physiol. 2024 Jun 1;326(6):F917-F930. doi: 10.1152/ajprenal.00320.2022. Epub 2024 Apr 18.


Cannabis and synthetic cannabinoid consumption are increasing worldwide. Cannabis contains numerous phytocannabinoids that act on the G protein-coupled cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 expressed throughout the body, including the kidney. Essentially every organ, including the kidney, produces endocannabinoids, which are endogenous ligands to these receptors. Cannabinoids acutely increase urine output in rodents and humans, thus potentially influencing total body water and electrolyte homeostasis. As the kidney collecting duct (CD) regulates total body water, acid/base, and electrolyte balance through specific functions of principal cells (PCs) and intercalated cells (ICs), we examined the cell-specific immunolocalization of CB1R in the mouse CD. Antibodies against either the C-terminus or N-terminus of CB1R consistently labeled aquaporin 2 (AQP2)-negative cells in the cortical and medullary CD and thus presumably ICs. Given the well-established role of ICs in urinary acidification, we used a clearance approach in mice that were acid loaded with 280 mM NH4Cl for 7 days and nonacid-loaded mice treated with the cannabinoid receptor agonist WIN55,212-2 (WIN) or a vehicle control. Although WIN had no effect on urinary acidification, these WIN-treated mice had less apical + subapical AQP2 expression in PCs compared with controls and developed acute diabetes insipidus associated with the excretion of large volumes of dilute urine. Mice maximally concentrated their urine when WIN and 1-desamino-8-d-arginine vasopressin [desmopressin (DDAVP)] were coadministered, consistent with central rather than nephrogenic diabetes insipidus. Although ICs express CB1R, the physiological role of CB1R in this cell type remains to be determined.NEW & NOTEWORTHY The CB1R agonist WIN55,212-2 induces central diabetes insipidus in mice. This research integrates existing knowledge regarding the diuretic effects of cannabinoids and the influence of CB1R on vasopressin secretion while adding new mechanistic insights about total body water homeostasis. Our findings provide a deeper understanding about the potential clinical impact of cannabinoids on human physiology and may help identify targets for novel therapeutics to treat water and electrolyte disorders such as hyponatremia and volume overload.

Keywords: cannabinoid; cannabis; kidney; vasopressin; water.

MeSH terms

  • Animals
  • Aquaporin 2* / metabolism
  • Benzoxazines* / pharmacology
  • Cannabinoid Receptor Agonists / pharmacology
  • Diabetes Insipidus, Neurogenic / metabolism
  • Diabetes Insipidus, Neurogenic / physiopathology
  • Disease Models, Animal
  • Diuresis* / drug effects
  • Kidney Tubules, Collecting* / drug effects
  • Kidney Tubules, Collecting* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines* / pharmacology
  • Naphthalenes* / pharmacology
  • Receptor, Cannabinoid, CB1* / metabolism


  • Receptor, Cannabinoid, CB1
  • Benzoxazines
  • Aquaporin 2
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Morpholines
  • Naphthalenes
  • Cannabinoid Receptor Agonists
  • CNR1 protein, mouse
  • Aqp2 protein, mouse