Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy

Barutta, Federica; Piscitelli, Fabiana; Pinach, Silvia; Bruno, Graziella; Gambino, Roberto; Rastaldi, Maria Pia; Salvidio, Gennaro; Marzo, Vincenzo Di; Perin, Paolo Cavallo; Gruden, Gabriella

doi:10.2337/db10-1809

Cited by 130 publications

(178 citation statements)

References 45 publications

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“…These changes are likely mediated by internalization of albumin and are not regulated by ERK1/2 signaling [52]. While CB 2 receptor expression is unaffected in STZ-induced diabetic mice and rats [51,52], its glomerular expression is downregulated in patients with advanced DN [51]. This observation could be explained by increased intraglomerular pressure, but not renal hyperglycemia.…”

Section: Role Of Cb 2 Receptor In Dnmentioning

confidence: 68%

“…Unlike a previous study by the same group, global deletion but not pharmacological CB 2 receptor activation regulates renal fibrosis. In their earlier study, Barutta et al [51] demonstrated that AM1241 does not ameliorate renal fibrosis, while their recent findings show that the expressions of fibronectin, type I collagen, and type IV α4 chain collagen are further enhanced in CB 2 -null diabetic mice [73], suggesting that pharmacological modulation of CB 2 receptor by AM1241 is not sufficient to protect against renal fibrosis. To clarify how monocyte infiltration could be a potential mediator in the genetic absence of CB 2 receptor and indirectly affects kidney function by releasing cytokines and reactive oxygen species (ROS), it is found that transplantation of CB 2 -null bone marrow cells does not magnify albuminuria, renal dysfunction, and/or fibrosis in STZtreated wild-type animals [73].…”

Section: Role Of Cb 2 Receptor In Dnmentioning

confidence: 96%

“…Chronic treatment of STZ-induced diabetic mice with the selective CB 2 agonist AM1241 ameliorates albuminuria and nephrin and zonula occludens-1 downregulation. Yet it does not affect glomerular hypertrophy or monocyte chemotactic protein 1 expression [51]. Likewise, CB 2 receptor deletion in STZ-treated mice exacerbates albuminuria, renal function, nephrin and podocin protein loss, and mesangial expansion [73].…”

Section: Role Of Cb 2 Receptor In Dnmentioning

confidence: 99%

“…While several groups were unable to detect its gene and protein expression in human and rat renal tissues [15,44], others reported that CB 2 receptors are expressed in human and rat renal cortex samples, with abundant expression in podocytes [51], proximal tubule cells [34,52,53], and rat mesangial cells [54].…”

Section: The Renal Ecb Systemmentioning

confidence: 99%

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The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases

Tam

2015

Journal of Basic and Clinical Physiology and Pharmacology

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Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana. The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB 1 and CB 2 , respectively), and the enzymes involved in their biosynthesis and degradation. It is present in both the central nervous system and peripheral organs including the kidney. The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies. Normally, activation of the CB 1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB 1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis. These effects can be chronically ameliorated by CB 1 receptor blockers. In contrast, activation of the renal CB 2 receptors reduces the deleterious effects of these chronic diseases. Because the therapeutic potential of globally acting CB 1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB 1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.Keywords: CB 1 receptor; CB 2 receptor; diabetic nephropathy; endocannabinoids; obesity; renal function. The endocannabinoid systemThe recreational, psychoactive, and medicinal effects of marijuana, many of which have important therapeutic potentials, have been recognized for thousands of years [1]. Yet, it is only in the last several decades that our understanding of these effects had grown following some landmark discoveries in the field of cannabinoid research. To date, more than 60 plant-derived cannabinoid molecules have been identified in marijuana [2], among which only Δ 9 -tetrahydrocannabinol (THC) is responsible for its psychoactive properties [3]. This initial discovery has allowed the synthesis of structurally modified molecules that have been used to study structure-activity relationships and reveal tight structural and steric selectivity in the biological actions of cannabinoids. Indeed, it took more than two decades to identify the THC binding site in the brain [4], which was later cloned and named cannabinoid-1 (CB 1 ) receptor [5]. In addition to the brain-type CB 1 receptor, a second cannabinoid receptor was identified in lymphoid tissue and was named CB 2 [6]. Both CB 1 and CB 2 receptors, which share a low level (44%) of sequence homology [6], are G protein-coupled receptors that mainly signal via G i /G o proteins, even though they may also activate G s , G q/11 , and G protein-independent signaling pathways [7]. These receptors are expressed in the brain [8][9][10], liver [11,...

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Section: Role Of Cb 2 Receptor In Dnmentioning

confidence: 68%

Section: Role Of Cb 2 Receptor In Dnmentioning

confidence: 96%

Section: Role Of Cb 2 Receptor In Dnmentioning

confidence: 99%

Section: The Renal Ecb Systemmentioning

confidence: 99%

See 2 more Smart Citations

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases

Tam

2015

Journal of Basic and Clinical Physiology and Pharmacology

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“…There is emerging evidence that activation of CB2 inhibits tissue inflammation and has analgesic properties [78][79][80]. The CB2 subtype is mainly expressed outside the CNS, as described earlier, so it can act as a potential endocannabinoid target where analgesic effects may be separated from psychotropic effects by activating the peripheral receptors.…”

Section: Cannabinoid Receptors As Therapeutic Targetsmentioning

confidence: 99%

Cannabinoids and the Urinary Bladder

Bakali¹

2013

Gynecol Obstet

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The presence of the Endocannabinoid System (ECS) in the urinary bladder has led to speculation that endocannabinoid-signalling is involved in the signal transduction pathways regulating bladder relaxation and may be involved in pathophysiological processes of the bladder. On the basis of this evidence, it was postulated that the binding of endocannabinoids to the cannabinoid receptors (CB 1 and CB 2 ) may result in relaxation of the urinary bladder during the filling phase. Dysregulation of the ECS in human bladder may be responsible for the aetiopathogenesis of Overactive Bladder Syndrome (OAB) and Detrusor Overactivity (DO).

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Redox Signalling and Role of Antioxidant in Heart and Kidney Disease

Sundaresan

Vasudevan

Albert

et al. 2018

Encyclopedia of Life Sciences

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Redox signalling refers to oxidation–reduction reactions involved in cellular signalling pathways. Reactive oxygen species (ROS) regulates various physiological, pathological and stress response pathways through redox signalling. Low level of ROS is responsible for cellular processes such as immune response, metabolism, transcriptional signalling, cell cycle, apoptosis and cell differentiation. Elevated levels of ROS lead to oxidative stress and imbalance in redox equilibrium. Disruption of redox homeostasis triggers the onset of metabolic disorders especially diabetes, cardiovascular and chronic kidney diseases causing organ damage. Endogenous antioxidants molecules such as superoxide dismutase (SOD), catalase, glutathione reductase (GRD) and glutathione peroxidase (GPx) play significant role under pathophysiological conditions in maintaining redox balance. In this article, the importance of redox‐activated NF‐E2‐related factor 2 (Nrf2) is discussed as an example for transcriptional antioxidant response. Thus understanding the mechanism behind the modulation of transcription factors and receptors may provide therapeutic interventions in redox‐related diseases. Key Concepts Cellular ROS sensing and metabolism are tightly regulated by a variety of signalling molecules involved in the redox (reduction/oxidation) mechanism. Oxidative stress refers to the imbalance due to excess ROS and the incapability of the cell to respond to an effective antioxidant. Redox signalling through H 2 O 2 activates prosurvival transcriptional pathways including Nrf2. Both NADPH oxidase and mitochondrial electron gradient play roles in hyperglycaemia‐induced ROS generation. Normal redox signalling is disrupted in diabetes leading to several pathological mechanisms that cause tissue damage and further leading to organ dysfunction. Enzymatic and nonenzymatic antioxidants defence system satiates ROS in heart. Nrf2/ARE (antioxidant response element) regulates expression of many detoxifying genes and confers protection against cardiac and vascular disorders. Imbalance between ROS and antioxidant enzymes results in pathology of chronic kidney disease. Hyperoxaluria plays an important role in excessive ROS generation leading to kidney damage. Modulation of cannabinoid receptors ameliorates chronic kidney disease.

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Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy

Cited by 130 publications

References 45 publications

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases

Cannabinoids and the Urinary Bladder

Redox Signalling and Role of Antioxidant in Heart and Kidney Disease

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