Modulation of P‐glycoprotein activity by cannabinoid molecules in HK‐2 renal cells

Nieri, Paola; Romiti, Nadia; Adinolfi, Barbara; Chicca, Andrea; Massarelli, Ilaria; Chieli, Elisabetta

doi:10.1038/sj.bjp.0706778

Cited by 30 publications

(32 citation statements)

References 39 publications

(42 reference statements)

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“…HK2 cells were treated with the global cannabinoid agonist anandamide (AEA: 0.1 μM and AEA 1 μM ). Dose ranges utilised were similar to those employed in previously published literature [24,[26][27][28][29][30]. Treatment groups were compared to vehicle control (ethanol 0.02%).…”

Section: Hypertrophy Assaymentioning

confidence: 99%

Role for Cannabinoid Receptors in Human Proximal Tubular Hypertrophy

Jenkin¹,

McAinch²,

Grinfeld³

et al. 2010

Cell Physiol Biochem

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Endogenous endocannabinoids bind to cannabinoid receptors; namely CB1, CB2, TRPV1 and GPR55, to activate intracellular pathways that control many cellular functions. Elevated levels of endocannabinoids have been identified in diseases such as obesity and diabetes, with the onset of diabetic nephropathy associated with proximal tubule hypertrophy. Recent research has identified a role for CB1 in apoptosis in human proximal tubular (HK2) cells, however the role of the other receptors has not been investigated. We investigated if the cannabinoid receptors played a role in hypertrophy in HK2 cells. Characterisation of HK2 cells demonstrated that mRNA and protein for CB1, CB2, TRPV1 and GPR55 occurs in these cells. Importantly, activation of the cannabinoid receptors with anandamide significantly increases hypertrophy in HK2 cells. In general, treatment with CB1 antagonist AM-251, reduces hypertrophy while treatment with CB2 (AM-630) and TRPV1 (SB-366791) antagonists increases hypertrophy. Targeting a cannabinoid receptor sensitive to O-1918 in HK2 cells did not alter proximal tubule cell hypertrophy. Therefore it is likely that in human proximal tubule, these receptors regulate cellular function by activating different cell signalling pathways. Nonetheless, we have identified a role for cannabinoid receptors in proximal tubule cells which may provide novel therapeutic targets for the treatment of diabetes and obesity.

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Section: Hypertrophy Assaymentioning

confidence: 99%

Role for Cannabinoid Receptors in Human Proximal Tubular Hypertrophy

Jenkin¹,

McAinch²,

Grinfeld³

et al. 2010

Cell Physiol Biochem

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“…Moreover, phloridzin is a specific inhibitor of SGLT1-mediated transport, but we do not believe that SGLT1 is involved in the uptake of a low concentration of serotonin [51] and dopamine [52] transporters. Cannabinoids also interfere with P-glycoprotein [53] , with an equilibrative nucleoside transporter [54] , and with the placental uptake of the vitamin folate [55] .…”

Section: Discussionmentioning

confidence: 99%

Lack of a Significant Effect of Cannabinoids upon the Uptake of 2-Deoxy-<i>D</i>-Glucose by Caco-2 Cells

Gonçalves¹,

Araújo²,

Azevedo³

et al. 2008

Pharmacology

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The endogenous cannabinoid system plays a role in the regulation of energy homeostasis acting through central pathways, and its dysregulation may be implicated in the pathogenesis of obesity. Recent evidence is accumulating showing that the endogenous cannabinoid system is also present in peripheral tissues. The aim of this work was to investigate the effect of cannabinoids upon the intestinal absorption of glucose. For this, we investigated the effect of some cannabinoid receptor agonists and antagonists upon the apical uptake of ³H-2-deoxy-D-glucose by the human intestinal epithelial Caco-2 cells. Uptake of a low concentration of ³H-2-deoxy-D-glucose (1 µmol/l) was both cytochalasin B- and phloridzin-sensitive. The maximal inhibition obtained with each of these inhibitors was 50%, and their effect was not cumulative. On the other hand, uptake of a high concentration of ³H-2-deoxy-D-glucose (20 mmol/l) was partially inhibited by cytochalasin B (±20%) and phloridzin had no effect. We verified that neither the cannabinoid receptor agonists [tetrahydrocannabinol (1–10 µmol/l), anandamide (0.1–10 µmol/l) and CP 55,940 (5 nmol/l to 1 µmol/l)], nor the specific CB₁ and CB₂ antagonists [AM251 (10–500 nmol/l) and AM630 (50 nmol/l to 1 µmol/l), respectively] had a significant effect upon ³H-2-deoxy-D-glucose uptake by Caco-2 cells. This was true for both the uptake of a low (1 µmol/l) and of a high (20 mmol/l) concentration of ³H-2-deoxy-D-glucose. From these results, we may hypothesize that cannabinoids do not interfere with the intestinal GLUT2-mediated apical uptake of glucose.

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“…Cannabinoids also interfere with P-glycoprotein [20] and with an equilibrative nucleoside transporter [21] . Interestingly, tetrahydrocannabinol (THC), the main psychoactive cannabinoid present in marijuana, was very recently found to interfere with the uptake of FA by primary cultures of human trophoblasts [6,22] .…”

Section: Introductionmentioning

confidence: 99%

“…This observation suggests that the effect of THC and anandamide is not mediated by the CB receptor. Interestingly enough, cannabinoids were previously shown to interfere with other transport mechanisms via CB-receptor-independent mechanisms [19][20][21] . So, it is possible that the effect of cannabinoids upon FA uptake results from a direct effect of the compounds on FA transporter(s).…”

mentioning

confidence: 99%

Effect of Cannabinoids upon the Uptake of Folic Acid by BeWo Cells

Araújo

Gonçalves

Martel³

2009

Pharmacology

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Folic acid (FA) is an essential micronutrient that is particularly important during pregnancy for normal placental and fetal development and growth. The placenta and the fetus become frequently exposed to drugs of abuse such as cannabinoids because of maternal use of these substances. The aim of this study was to investigate the influence of cannabinoids on the uptake of FA by BeWo cells. Acute treatment with anandamide (1–10 μmol/l) caused a 15% decrease in ³H-FA uptake at pH 7.5. Moreover, tetrahydrocannabinol (THC) (1–10 μmol/l) caused a 30% increase, and AM630 (1 μmol/l) a 15% decrease in this parameter at pH 6.5. Neither the inhibitory effect of anandamide nor the stimulatory effect of THC were changed in the presence of cannabi- noid receptor type 1 or type 2 antagonists (AM251 and AM630, respectively). Chronic treatment (48 h) with THC (100 nmol/l) and AM251 (100 nmol/l) decreased the uptake of ³H-FA by 20% at pH 7.5, and anandamide (1 μmol/l) and AM630 (10–500 nmol/l) increased it by 30%. Moreover, CP55,940 (10 nmol/l) increased the uptake of ³H-FA by 30% at pH 6.5. RT-PCR analysis showed that the mRNA levels of the reduced folate transporter 1 increased by 9% after chronic treatment with AM630 (500 nmol/l). The mRNA levels of the proton-coupled folate transporter decreased by 17% and increased by 18% after chronic treatment with THC (0.1 μmol/l) and AM251 (100 nmol/l), respectively. In conclusion, ³H-FA uptake by BeWo cells is significantly, although not very markedly, changed by several distinct CB receptor agonists and antagonists, both after acute and chronic exposure of the cells. The acute effects of cannabinoid receptor agonists do not seem to be mediated by the cannabinoid receptor, and with a few exceptions the chronic effects do not seem to be related to changes in the expression levels of FA transporters.

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Modulation of P‐glycoprotein activity by cannabinoid molecules in HK‐2 renal cells

Cited by 30 publications

References 39 publications

Role for Cannabinoid Receptors in Human Proximal Tubular Hypertrophy

Role for Cannabinoid Receptors in Human Proximal Tubular Hypertrophy

Lack of a Significant Effect of Cannabinoids upon the Uptake of 2-Deoxy-<i>D</i>-Glucose by Caco-2 Cells

Effect of Cannabinoids upon the Uptake of Folic Acid by BeWo Cells

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