Localization and Functional Characterization of the Cannabinoid Receptor Type 1 (CB1R) in the Kidney
Introduction Cannabis and synthetic cannabinoid consumption is increasing worldwide. The impact of their consumption on human health including the risk of kidney disease and its associated complications is uncertain. The kidney, among other organs, produces endogenous cannabinoids (endocannabinoids, ECs) that act on the G‐protein‐coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). ECs and CB1R agonists acutely act as diuretics with variable effects on Na+, K+, and HCO3– excretion. As the aldosterone sensitive distal nephron (ASDN) is responsible for the final renal regulation of total body electrolyte, acid/base, and water balance that is mediated by principal cells (PCs) and intercalated cells (ICs), we sought to examine the cell specific expression of components of the EC system in the mouse collecting duct and the acute changes in urine composition after administration of the cannabinoid receptor agonist WIN55,212‐2 (WIN). Methods CB1R and AQP2 localization were examined by immunofluorescence microscopy in cryosections of kidneys harvested from non‐manipulated male C57BL/6 mice (7‐12 weeks of age) using protein‐specific Abs. A subset of whole animal metabolic studies were performed in mice that were acid‐loaded by provision of 20 mM NH4 Cl and 1% sucrose added to the drinking water x 7d. On the day of experimentation, mice were allowed to spontaneously void, then injected SC with either 1.5 mg/kg WIN or vehicle control (10% Tween‐80 and 10% DMSO in 1x PBS) in a volume <1% BW. Urine was collected for up to 4hr for measurement of volume, pH, osmolality, Na+ and K+. Results In the ASDN, CB1R was localized to AQP2(‐) cells, and thus presumably ICs. Acid‐loaded mice treated with WIN (n=5) had similar U pH, U Na V, and U K V to untreated mice (n= 4) but had a higher urine output (UOP) (24.1 ± 6.5 vs. 13.6 ±1.2 µL/gBW/4hr; (P=0.02) and a lower U Osm(822 ± 335 vs. 1912 ± 293 mmol/kg H2 O; P=0.001). WIN‐treated non‐acid loaded mice (n=7) urinated more frequently (3.6 ± 2.2 vs. 0.4 ± 0.5 micturitions/2 hr; P=0.05), had a lower U Osm(315 ± 82 vs. 1449 ± 553 mmol/kg H2 O; P<0.0001), and lower U K V (0.4 ± 0.2 vs. 0.9 ± 0.3 µmol/gBW/2hrs; P=0.002) compared to controls (n=8), whereas U Na V and U pH were similar. Furthermore, WIN reduced the apical/cytoplasmic ratio of AQP2 expression in PCs of the inner medulla by 43% (n=209 cells in 4 mice) compared to controls (n=183 cells in 4 mice) (P<0.0001). Conclusion ICs express CB1R. Although U pH and Na+ excretion were unaffected in either acid‐loaded or non‐acid loaded mice by WIN, the cannabinoid receptor agonist induced diabetes insipidus, a disorder characterized by the excretion of large volumes of dilute urine, and reduced K+ excretion in non‐acid loaded mice. Efforts are underway to determine whether this effect is central or nephrogenic. These results promise to reveal how cannabis affects kidney function and to identify potential targets for novel therapeutics to treat water and electrolyte disorders..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
The FASEB Journal - 36(2022) |
| Beteiligte Personen: |
Rein, Joshua L. [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
© 2022 Federation of American Societies for Experimental Biology |
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| Umfang: |
1 |
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| doi: |
10.1096/fasebj.2022.36.S1.L7733 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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WLY006591329 |
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| 520 | |a Introduction Cannabis and synthetic cannabinoid consumption is increasing worldwide. The impact of their consumption on human health including the risk of kidney disease and its associated complications is uncertain. The kidney, among other organs, produces endogenous cannabinoids (endocannabinoids, ECs) that act on the G‐protein‐coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). ECs and CB1R agonists acutely act as diuretics with variable effects on Na+, K+, and HCO3– excretion. As the aldosterone sensitive distal nephron (ASDN) is responsible for the final renal regulation of total body electrolyte, acid/base, and water balance that is mediated by principal cells (PCs) and intercalated cells (ICs), we sought to examine the cell specific expression of components of the EC system in the mouse collecting duct and the acute changes in urine composition after administration of the cannabinoid receptor agonist WIN55,212‐2 (WIN). Methods CB1R and AQP2 localization were examined by immunofluorescence microscopy in cryosections of kidneys harvested from non‐manipulated male C57BL/6 mice (7‐12 weeks of age) using protein‐specific Abs. A subset of whole animal metabolic studies were performed in mice that were acid‐loaded by provision of 20 mM NH4 Cl and 1% sucrose added to the drinking water x 7d. On the day of experimentation, mice were allowed to spontaneously void, then injected SC with either 1.5 mg/kg WIN or vehicle control (10% Tween‐80 and 10% DMSO in 1x PBS) in a volume <1% BW. Urine was collected for up to 4hr for measurement of volume, pH, osmolality, Na+ and K+. Results In the ASDN, CB1R was localized to AQP2(‐) cells, and thus presumably ICs. Acid‐loaded mice treated with WIN (n=5) had similar U pH, U Na V, and U K V to untreated mice (n= 4) but had a higher urine output (UOP) (24.1 ± 6.5 vs. 13.6 ±1.2 µL/gBW/4hr; (P=0.02) and a lower U Osm(822 ± 335 vs. 1912 ± 293 mmol/kg H2 O; P=0.001). WIN‐treated non‐acid loaded mice (n=7) urinated more frequently (3.6 ± 2.2 vs. 0.4 ± 0.5 micturitions/2 hr; P=0.05), had a lower U Osm(315 ± 82 vs. 1449 ± 553 mmol/kg H2 O; P<0.0001), and lower U K V (0.4 ± 0.2 vs. 0.9 ± 0.3 µmol/gBW/2hrs; P=0.002) compared to controls (n=8), whereas U Na V and U pH were similar. Furthermore, WIN reduced the apical/cytoplasmic ratio of AQP2 expression in PCs of the inner medulla by 43% (n=209 cells in 4 mice) compared to controls (n=183 cells in 4 mice) (P<0.0001). Conclusion ICs express CB1R. Although U pH and Na+ excretion were unaffected in either acid‐loaded or non‐acid loaded mice by WIN, the cannabinoid receptor agonist induced diabetes insipidus, a disorder characterized by the excretion of large volumes of dilute urine, and reduced K+ excretion in non‐acid loaded mice. Efforts are underway to determine whether this effect is central or nephrogenic. These results promise to reveal how cannabis affects kidney function and to identify potential targets for novel therapeutics to treat water and electrolyte disorders. | ||
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