# The regulation of renal tubular transport by cannabinoid receptor type 1 (CB1R) and its endogenous lipid ligands

> **NIH VA IK2** · JAMES J PETERS VA  MEDICAL CENTER · 2024 · —

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Cannabis is the most commonly used federally illicit recreational drug in the U.S., and legal recreational and
medicinal use has increased over the last decade. Cannabis contains phytocannabinoids with differing affinities
for the ubiquitously expressed G-protein coupled cannabinoid receptors CB1R and CB2R. The kidney produces
endogenous cannabinoids (ECs) that increase urine output with variable effects on Na+ and K+ excretion in
rodents. Few studies in humans suggest that cannabinoids can act as diuretics, promoting not only urinary Na+
but alsoHCO3- losses. We have preliminarily shown in mice that CB1R is expressed in and impairs pHi regulation
in intercalated cells (ICs), cells in the cortical collecting duct (CCD) that are responsible for H+/HCO3- secretion
and Na+ (and K+) transport. We have also shown that cannabinoid receptor agonists acutely increase urinary
water excretion in mice. Therefore, we hypothesize that ICs participate in CB1R mediated diuresis possibly
through cross-talk with principal cells, cells responsible for the reabsorption of Na+ and water.
This VA Career Development Award application aims to define the role of ECs in the CCD. Three Specific
Aims (SA) will be studied to evaluate the presence and physiological significance of CB1R signaling on function
of the mouse CCD. SA1 will define cell-specific expression of components of the EC system in this segment;
SA2 will determine the role of CB1R signaling on cell-specific function in the CCD, utilizing pharmacologic
activators/inhibitors of CB1R; and SA3 will determine whether targeted deletion of CB1R in ICs alters cell-specific
functions. The results promise to provide new insight into the effects of cannabinoids on the kidney and allows
us to identify targets (e.g., CB1R agonists) for development of novel therapeutic agents for the treatment of
disorders such as hypertension, volume overload, metabolic acidosis, and hyponatremia.
 The proposed training plan includes career development activities, courses, and workshops to enhance the
proficiency of the PI (Dr. Joshua Rein, a board-certified nephrologist and certified hypertension specialist) in
single tubule microdissection, isolated tubule in vitro microperfusion, functional fluorescent microscopy, lipid
biochemistry and pharmacology, cell biology, electrophysiology, cell sorting, and animal models including the
development of transgenic mouse models. These skills will be reinforced by a team of mentors, advisors, and
collaborators, all of whom have the requisite expertise, knowledge, and mentorship track-records.
In sum, this VA CDA grant proposal provides a robust career development plan for Dr. Rein to accomplish
his career goals to develop a national reputation as an expert in the renal EC system, aiming to uncover novel
molecular pathways underlying the renal regulation of electrolyte and acid/base balance. His long-term goal is
to translate key observations from preclinical studies into...

## Key facts

- **NIH application ID:** 10866340
- **Project number:** 5IK2BX006144-02
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** Joshua L Rein
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866340

## Citation

> US National Institutes of Health, RePORTER application 10866340, The regulation of renal tubular transport by cannabinoid receptor type 1 (CB1R) and its endogenous lipid ligands (5IK2BX006144-02). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10866340. Licensed CC0.

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