Cannabinoid‐1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

Drori, Adi; Permyakova, Anna; Hadar, Rivka; Udi, Shiran; Nemirovski, Alina; Tam, Joseph

doi:10.1111/dom.13497

Cited by 34 publications

(37 citation statements)

References 74 publications

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“…Nevertheless, we could not completely rule out the obligatory role of CB 1 receptors in modulating renal oxidative stress as well, because knocking it out in RPTCs protected the cells from O:P-induced lipid oxidation and oxidative stress. These results support our previous findings in mice lacking CB 1 receptors specifically in RPTCs, which are completely protected from the deleterious effects of HFD feeding and fatty acid flux-induced renal dysfunction, inflammation, mitochondrial damage, oxidative stress, and fibrosis (Drori et al, 2019;Udi et al, 2017).…”

Section: Discussionsupporting

confidence: 92%

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Udi

Hinden

Ahmad

et al. 2019

British J Pharmacology

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Background and Purpose: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB 1 receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB 1 receptors and iNOS may serve as an effective therapeutic agent against obesity-induced CKD.Experimental Approach: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB 1 receptor/iNOS antagonist, MRI-1867(3 mg·kg −1 ), in ameliorating obesity-induced CKD, and compared its metabolic and renal efficacies to a stand-alone peripheral CB 1 receptor antagonist (JD5037; 3 mg·kg −1 ), iNOS antagonist (1400W; 10 mg·kg −1 ), and pair feeding. Mice with highfat diet-induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet-fed mice treated with Veh served as controls.Key Results: Enhanced expression of CB 1 receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB 1 receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling.Conclusions and Implications: Collectively, our results highlight the therapeutic relevance of blocking CB 1 receptors and iNOS in ameliorating obesity-induced CKD.---

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Section: Discussionsupporting

confidence: 92%

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Udi

Hinden

Ahmad

et al. 2019

British J Pharmacology

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“…This comes in addition to previous reports of non-receptor specific effect of cannabinoids on mitochondria [89,90]. Interestingly, it has been shown that the CB1-mediated effect on mitochondrial dynamics is not restricted to cells of the nervous system [91]. In this study, it is shown that CB1 stimulation by the endocannabinoid, n-arachidonoylethanolamine (AEA), in renal proximal tubular cells leads to dynamin-related protein 1 (DRP1) activation, with its subsequent translocation to the mitochondria that results in mitochondrial fission.…”

Section: Cannabinoids Mitochondria and The Nervous Systemsupporting

confidence: 71%

Cannabinoid-Induced Immunomodulation during Viral Infections: A Focus on Mitochondria

Beji

Loucif

Telittchenko

et al. 2020

Viruses

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This review examines the impact of cannabinoids on viral infections, as well as its effects on the mitochondria of the nervous and immune system. The paper conveys information about the beneficial and negative impacts of cannabinoids on viral infections, especially HIV-1. These include effects on the inflammatory response as well as neuroprotective effects. We also explore non-apoptotic mitochondrial pathways modulated by the activity of cannabinoids, resulting in modifications to cellular functions. As a large part of the literature derives from studies of the nervous system, we first compile the information related to mitochondrial functions in this system, particularly through the CB1 receptor. Finally, we reflect on how this knowledge could complement what has been demonstrated in the immune system, especially in the context of the CB2 receptor and Ca2+ uptake. The overall conclusion of the review is that cannabinoids have the potential to affect a broad range of cell types through mitochondrial modulation, be it through receptor-specific action or not, and that this pathway has a potential implication in cases of viral infection.

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“…eCBs were extracted, purified, and quantified in liver homogenates, as described previously ( Drori et al, 2019 ; Udi et al, 2017 ). LC-MS/MS was analyzed on an AB Sciex (Framingham, MA, USA) Triple Quad 5500 mass spectrometer coupled with a Shimadzu (Kyoto, Japan) UHPLC System.…”

Section: Methodsmentioning

confidence: 99%

CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

Drori

Gammal

Azar

et al. 2020

eLife

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The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.

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Cannabinoid‐1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

Abstract: CB R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in the organelle's function and contributing to the renal tubular injury associated with lipotoxicity and other metabolic diseases.

Cited by 34 publications

References 74 publications

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Cannabinoid-Induced Immunomodulation during Viral Infections: A Focus on Mitochondria

CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

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Cannabinoid‐1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

Abstract: CB R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in the organelle's function and contributing to the renal tubular injury associated with lipotoxicity and other metabolic diseases.

Cited by 34 publications

References 74 publications

Dual inhibition of cannabinoid CB1 receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Dual inhibition of cannabinoid CB1 receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Cannabinoid-Induced Immunomodulation during Viral Infections: A Focus on Mitochondria

CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

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Product

Resources

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Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease