Angiotensin II Induces Vascular Endocannabinoid Release, Which Attenuates Its Vasoconstrictor Effect via CB1 Cannabinoid Receptors

Szekeres, Mária; Nádasy, György L.; Turu, Gábor; Soltész‐Katona, Eszter; Tóth, Zsuzsanna; Balla, András; Catt, Kevin J.; Hunyady, László

doi:10.1074/jbc.m112.346296

Cited by 50 publications

(73 citation statements)

References 49 publications

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“…8). Similar to the present findings, activation of Agtr1 induced CB 1 Rmediated effects in other tissues via increasing the synthesis of the endocannabinoid 2-arachidonoyl glycerol (49,50), whereas CB 1 R blockade was found to down-regulate AGT1R (51). There is also evidence that CB 1 R involvement in angiotensin IIinduced pathologies may reflect Agtr1/CB 1 R heteromerization, a process which amplifies Agtr1 signaling (52).…”

Section: Discussionsupporting

confidence: 89%

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

Jourdan¹,

Szanda²,

Rosenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

145

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Diabetic nephropathy is a major cause of end-stage kidney disease, and overactivity of the endocannabinoid/cannabinoid 1 receptor (CB 1 R) system contributes to diabetes and its complications. Zucker diabetic fatty (ZDF) rats develop type 2 diabetic nephropathy with albuminuria, reduced glomerular filtration, activation of the reninangiotensin system (RAS), oxidative/nitrative stress, podocyte loss, and increased CB 1 R expression in glomeruli. Peripheral CB 1 R blockade initiated in the prediabetic stage prevented these changes or reversed them when animals with fully developed diabetic nephropathy were treated. Treatment of diabetic ZDF rats with losartan, an angiotensin II receptor-1 (Agtr1) antagonist, attenuated the development of nephropathy and down-regulated renal cortical CB 1 R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB 1 R and desmin gene expression were increased and podocin and nephrin content were decreased by either the CB 1 R agonist arachydonoyl-2′-chloroethylamide, angiotensin II, or high glucose, and the effects of all three were antagonized by CB 1 R blockade or siRNA-mediated knockdown of CNR1 (the cannabinoid type 1 receptor gene). We conclude that increased CB 1 R signaling in podocytes contributes to the development of diabetic nephropathy and represents a common pathway through which both hyperglycemia and increased RAS activity exert their deleterious effects, highlighting the therapeutic potential of peripheral CB 1 R blockade.iabetic nephropathy, a highly prevalent and serious complication of both type 1 and type 2 diabetes mellitus and a leading cause of renal failure, is characterized by albuminuria, decreased glomerular filtration rate (GFR), mesangial expansion, thickening of the glomerular basement membrane, and glomerular sclerosis (1). Multiple mechanisms have been implicated in the development of diabetic nephropathy, including activation of the renin-angiotensin system (RAS) (2), increase in oxidative (3) and nitrosative/nitrative stress (4), as well as an increase in local inflammation (5).The endocannabinoid system plays a well-documented role in obesity and its metabolic complications, including insulin resistance and type 2 diabetes (T2DM). Globally acting cannabinoid 1 receptor (CB 1 R) antagonists/inverse agonists improve obesity-related insulin resistance, dyslipidemia, fatty liver, and β-cell loss, and attenuate obesity-related inflammatory changes both in preclinical models of diet-induced or genetic obesity and in clinical trials in overweight subjects with metabolic syndrome (reviewed in refs. 6 and 7). Global CB 1 R blockade also has beneficial effects in mouse models of type 1 and type 2 diabetic nephropathy (8-11). However, the therapeutic development of this class of compounds has been halted because of adverse neuropsychiatric side effects in a small proportion of treated subjects (12). Recent studies in rodent models have demonstrated that peripherally restricted CB 1 R antagonists are as effective as globally acti...

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Section: Discussionsupporting

confidence: 89%

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

Jourdan¹,

Szanda²,

Rosenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

145

View full text Add to dashboard Cite

show abstract

“…The receptor plays role in many important physiological processes, such as learning, thinking, nociception or the regulation of food-intake (Pacher et al, 2006). Activation of presynaptic CB 1 Rs by postsynaptic endocannabinoid release, which mediates retrograde transmission, is a key regulatory mechanism in the central nervous system, but paracrine activation of CB 1 Rs with a similar mechanism can also occur in extraneural tissues (Freund et al, 2003;Gyombolai et al, 2012;Sanchez et al, 2001;Turu et al, 2009;Szekeres et al, 2012). The cellular signaling events following CB 1 R activation are mainly associated with the activation of heterotrimeric G i/o -proteins and include inhibition of adenylyl cyclases, activation of K ir channels, inhibition of Ca v channels and phosphorylation and activation of different subtypes of mitogen-activated protein kinases (MAP kinases) (Turu and Hunyady, 2010).…”

mentioning

confidence: 99%

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Gyombolai

Boros

Hunyady

et al. 2013

Molecular and Cellular Endocrinology

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CB 1 cannabinoid receptor (CB 1 R) undergoes both constitutive and agonist-induced internalization, but the underlying mechanisms of these processes and the role of β-arrestins in the regulation of CB 1 R function are not completely understood. In this study, we followed CB 1 R internalization using confocal microscopy and bioluminescence resonance energy transfer measurements in HeLa and Neuro-2a cells. We found that upon activation CB 1 R binds β-arrestin2 (β-arr2), but not β-arrestin1. Furthermore, both the expression of dominant-negative β-arr2 (β-arr2-V54D) and siRNA-mediated knock-down of β-arr2 impaired the agonist-induced internalization of CB 1 R. In contrast, neither β-arr2-V54D nor β-arr2-specific siRNA had a significant effect on the constitutive internalization of CB 1 R. However, both constitutive and agonist-induced internalization of CB 1 R were impaired by siRNA-mediated depletion of clathrin heavy chain. We conclude that although clathrin is required for both constitutive and agonist-stimulated internalization of CB 1 R, β-arr2 binding is only required for agonist-induced internalization of the receptor suggesting that the molecular mechanisms underlying constitutive and agonist-induced internalization of CB 1 R are different.

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“…Er-Ning Su et al also highlighted the critical role of the endothelium in cannabinoid-induced vasoactivity in isolated perfused retinal arterioles [15]. However, other studies have suggested that R-(+)-WIN55212-2-induced relaxation is endothelium independent in other vessels, including the rat small mesenteric artery [43] and gracilis arterioles [21]. Interestingly, using the bovine ophthalmic artery, Romano et al demonstrated that both endothelium-dependent and -independent pathways are involved in cannabinoid-agonist-induced relaxation [17].…”

Section: Discussionmentioning

confidence: 99%

Cannabinoids Regulate the Diameter of Pericyte-Containing Retinal Capillaries in Rats

Zong

Zhou

Cheng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cannabinoids are vasoactive substances that act as key regulators of arterial tone in the blood vessels supplying peripheral tissues and the central nervous system. We therefore investigated the effect of cannabinoids on retinal capillaries and pericytes. Methods: The effects of cannabinoids on capillary diameters were determined using an ex vivo whole-mount rat retinal model. Western blotting, quantitative PCR, and immunohistochemistry were performed to explore the underlying mechanism. Results: Endogenous cannabinoid 2-arachidonoylglycerol and anandamide and exogenous cannabinoid (R-(+)-WIN55212-2) dilated the noradrenaline-precontracted capillaries in a concentration-dependent manner (1 µM to 0.1 mM). The extent of vasorelaxation was positively correlated with changes in pericyte width. The effects of R-(+)-WIN55212-2 on vasorelaxation and pericyte width were inhibited by a cannabinoid receptor type-1 (CB1) antagonist, AM251 or rimonabant (SR141716A), the nitric oxide synthase inhibitor l-NAME, and the guanylate cyclase inhibitor ODQ. They were also abolished by the removal of the endothelium, but not by the cannabinoid receptor-2 antagonist SR144528, the endothelial cannabinoid receptor antagonist O-1918, or the cyclooxygenase inhibitor indomethacin. Conclusion: The exogenous cannabinoid R-(+)-WIN55212-2 promotes the vasorelaxation of pericyte-containing rat retinal capillaries. This effect of R-(+)-WIN55212-2 is dependent on CB₁ and the nitric oxide–cyclic guanosine monophosphate pathway, and requires an intact endothelium.

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Angiotensin II Induces Vascular Endocannabinoid Release, Which Attenuates Its Vasoconstrictor Effect via CB1 Cannabinoid Receptors

Cited by 50 publications

References 49 publications

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Cannabinoids Regulate the Diameter of Pericyte-Containing Retinal Capillaries in Rats

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