Induction of Proteinuria by Cannabinoid Receptors 1 Signaling Activation in CB1 Transgenic Mice

Lei, Chen-Chou; Shih, Ya‐Hsueh; Lin, Chun‐Liang; Hsu, Yung‐Chien; Ho, Cheng

doi:10.1097/maj.0000000000000352

Cited by 22 publications

(22 citation statements)

References 33 publications

(30 reference statements)

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“…We have found that AM251 treatment in obese rats was able to significantly reduce hyperleptinaemia induced by obesity, similar to a previous study (Tam et al 2012). Our findings are further supported by a recent study, which employed a transgenic mouse model to overexpress CB 1 and was shown that animals exhibited higher levels of proteinuria without alterations in blood glucose compared with the WT group (Hsu et al 2014). Prior to this study, the investigation of modulation of CB 1 as a therapeutic target in obesity-related renal dysfunction has only been studied in obese Zucker rats (Janiak et al 2007).…”

Section: Discussionsupporting

confidence: 79%

“…Previous studies have established that fibrotic markers including TGFB1, collagen IV and VEGFA are up-regulated in the kidney in obesity-related nephropathy (Jiang et al 2005, Cignarelli & Lamacchia 2007, Mathew et al 2011, Briffa et al 2013, Nolan et al 2013, Zhang et al 2013. Indeed, it has been shown that in lean transgenic mice that overexpress CB 1 , there is an increase in glomerular expression of VEGFA (Hsu et al 2014). However, we have demonstrated that, in AM251-treated obese rats, there is no significant alteration in renal expression of collagen IV, TGFB1 or VEGFA.…”

Section: Discussioncontrasting

confidence: 44%

“…The lack of change of megalin in the AM251-treated obese rats, which also exhibited reduced tubular hypertrophy, may have allowed a higher capacity for the binding of megalin to albumin in the filtrate, leading to the improved reabsorption and reduced urinary albumin excretion compared with obese control rats. Previous research in diabetic nephropathy has attributed improved renal function primarily to glomerular changes, with reduced loss of nephrin and podocin, observed in AM251-treated animals (Barutta et al 2010, Hsu et al 2014. Albumin is filtered by the glomerulus and largely reabsorbed by proximal tubule cells, and damage to either of these structures can result in albuminuria (Birn & Christensen 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in animal models of diabetic nephropathy, CB 1 antagonism ameliorates proteinuria, albuminuria and plasma creatinine, and improves creatinine clearance in diabetic animals (Janiak et al 2007, Barutta et al 2010, Nam et al 2012. In contrast, transgenic mice that overexpress CB 1 exhibit significant increases in proteinuria and kidney weight compared with WT mice (Hsu et al 2014). Therefore, modulation of CB 1 appears to be an effective mechanism for the reduction of the pathophysiological changes associated with nephropathy.…”

Section: Introductionmentioning

confidence: 98%

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Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

Jenkin¹,

O’Keefe²,

Simcocks³

et al. 2015

Journal of Endocrinology

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Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB 1 ) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB 1 antagonist AM251 in a model of DIO. Male Sprague-Dawley rats were fed a low-or high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks to elicit DIO (nZ9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (nZ9) or saline via i.p. injection (nZ9). After 10 weeks consuming a HFD, CB 1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB 1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB 1 antagonist AM251 improves renal outcomes in obese rats.

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Section: Discussionsupporting

confidence: 79%

Section: Discussioncontrasting

confidence: 44%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

Jenkin¹,

O’Keefe²,

Simcocks³

et al. 2015

Journal of Endocrinology

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show abstract

“…Because proteinuria is an independent predictor of renal outcome in patients with type 1 DM [64], a recent study tested the specific role of CB 1 receptors in mediating urinary protein excretion. Using a genetic CB 1 activation mouse model and pharmacological stimulation of CB 1 in rats, Hsu et al [65] showed that CB 1 receptor activation/stimulation increases urinary protein levels and is associated with enhanced glomerular CB 1 and vascular endothelial growth factor (VEGF) expression levels, as well as a subsequent reduction in nephrin gene and protein expression levels, suggesting a CB 1 /VEGFdependent signaling pathway that may lead to podocyte dysfunction and proteinuria.…”

Section: Role Of Cb 1 Receptors In Dnmentioning

confidence: 99%

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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Genetic Manipulation of the Endocannabinoid System

Zimmer

2015

Handbook of Experimental Pharmacology

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The physiological and pathophysiological functions of the endocannabinoid system have been studied extensively using transgenic and targeted knockout mouse models. The first gene deletions of the cannabinoid CB(1) receptor were described in the late 1990s, soon followed by CB(2) and FAAH mutations in early 2000. These mouse models helped to elucidate the fundamental role of endocannabinoids as retrograde transmitters in the CNS and in the discovery of many unexpected endocannabinoid functions, for example, in the skin, bone and liver. We now have knockout mouse models for almost every receptor and enzyme of the endocannabinoid system. Conditional mutant mice were mostly developed for the CB(1) receptor, which is widely expressed on many different neurons, astrocytes and microglia, as well as on many cells outside the CNS. These mouse strains include "floxed" CB(1) alleles and mice with a conditional re-expression of CB(1). The availability of these mice made it possible to decipher the function of CB(1) in specific neuronal circuits and cell populations or to discriminate between central and peripheral effects. Many of the genetic mouse models were also used in combination with viral expression systems. The purpose of this review is to provide a comprehensive overview of the existing genetic models and to summarize some of the most important discoveries that were made with these animals.

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Induction of Proteinuria by Cannabinoid Receptors 1 Signaling Activation in CB1 Transgenic Mice

Cited by 22 publications

References 33 publications

Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

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

Genetic Manipulation of the Endocannabinoid System

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