Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy.

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“Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.”

https://www.ncbi.nlm.nih.gov/pubmed/29030466

http://jasn.asnjournals.org/content/early/2017/10/12/ASN.2017040371

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Cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression.

Journal of Cancer Research and Clinical Oncology

“Renal cell carcinoma (RCC) is the most common malignancy of urogenital system, and patients with RCC may face a poor prognosis. However, limited curable therapeutic options are currently available.

The aim of this study is to investigate the role of Cannabinoid receptor 2 (CB2) in RCC progression.

CB2 expression is functionally related to cellular proliferation, migration, and cell cycle of RCC cells.

Our data suggest that CB2 might be a potential therapeutic target for RCC.”

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The role of cannabinoid receptors in renal diseases.

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“Chronic kidney disease (CKD) remains a major challenge for Public Health systems and corresponds to the replacement of renal functional tissue by extra-cellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for CKD except nephroprotective strategies.

The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in CKD.

Our review will first focus on the current state of knowledge regarding the cannabinoid system in normal renal physiology and in various experimental nephropathies, especially diabetes.  We will review the data obtained in models of diabetes and obesity as well as in nonmetabolic models of renal fibrosis and emphasizes the promising role of CB1 blockers and CB2 agonists in the development of renal disease and fibrosis. Next, we will review the current state of knowledge regarding the cellular pathways involved in renal fibrogenesis and renal injury.

Overall, this review will highlight the therapeutic potential of targeting the cannabinoid receptors in CKD and diabetes.”

https://www.ncbi.nlm.nih.gov/pubmed/28901271

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Increased Renal 2-Arachidonoylglycerol Level Is Associated with Improved Renal Function in a Mouse Model of Acute Kidney Injury.

Mary Ann Liebert, Inc. publishers

“Acute kidney injury (AKI) is associated with a significantly increased risk of morbidity and mortality. Ischemia-reperfusion injury (IRI) is a major cause of AKI. In this study, we investigated the role of the endocannabinoid (EC) system in renal IRI using a well-established mouse model.

Results: Renal IRI was associated with significantly increased serum BUN and creatinine, increased tubular damage score, increased expression of renal markers of inflammation and oxidative stress and elevated renal 2-AG content. Pretreatment with JZL184 was associated with a significant increase in renal 2-AG content and there was also improved serum BUN, creatinine and tubular damage score. However, renal expression of inflammation and oxidative stress markers remained unchanged.

Conclusions: This is the first report documenting that renal IRI is associated with an increase in kidney 2-AG content. Further enhancement of 2-AG levels using JZL184 improved indices of renal function and histology, but did not lower renal expression of markers of inflammation and oxidative stress. Further studies are needed to determine the mechanisms responsible for the effects observed and the potential value of 2-AG as a therapeutic target in renal IRI.”

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Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD.

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“Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.”

https://www.ncbi.nlm.nih.gov/pubmed/28860163

http://jasn.asnjournals.org/content/early/2017/08/30/ASN.2016101085

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Targeting cannabinoid signaling for peritoneal dialysis-induced oxidative stress and fibrosis.

“Long-term exposure to bioincompatible peritoneal dialysis (PD) solutions frequently results in peritoneal fibrosis and ultrafiltration failure, which limits the life-long use of and leads to the cessation of PD therapy. Therefore, it is important to elucidate the pathogenesis of peritoneal fibrosis in order to design therapeutic strategies to prevent its occurrence. Peritoneal fibrosis is associated with a chronic inflammatory status as well as an elevated oxidative stress (OS) status. Beyond uremia per se, OS also results from chronic exposure to high glucose load, glucose degradation products, advanced glycation end products, and hypertonic stress. Therapy targeting the cannabinoid (CB) signaling pathway has been reported in several chronic inflammatory diseases with elevated OS. We recently reported that the intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2receptor agonists, ameliorated dialysis-related peritoneal fibrosis. As targeting the CB signaling pathway has been reported to be beneficial in attenuating the processes of several chronic inflammatory diseases, we reviewed the interaction among the cannabinoid system, inflammation, and OS, through which clinicians ultimately aim to prolong the peritoneal survival of PD patients.”

https://www.ncbi.nlm.nih.gov/pubmed/28540200

http://www.wjgnet.com/2220-6124/full/v6/i3/111.htm

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Diuretic effects of cannabinoid agonists in mice

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“Cannabinoids both increase urine output and decrease urinary frequency in human subjects. However, these effects have not been systematically evaluated in intact mice, a species commonly used to evaluate the effects of novel cannabinoids.

The present studies investigated whether cannabinoid agonists reliably produce diuresis in mice at doses comparable to those that produce other cannabinoid effects and, further, identified the receptors that may mediate these effects.

These findings suggest that mice may provide a model for understanding the mixed effects of marijuana on urine output, as described in clinical studies, and aid in the development of targeted cannabinoid based therapies for bladder dysfunction.

Clinical studies have reported beneficial effects of smoked or aerosolized cannabis on bladder dysfunction in patients with multiple sclerosis, primarily by decreasing urinary frequency in these subjects following marijuana use. These reports contrast with the earlier clinical reports demonstrating increase in urine output after cannabis administration.

Our findings in mice demonstrate a dose related increase or decrease in urine output, providing a platform for understanding the mixed effects on urine output observed with marijuana in various clinical studies. As noted earlier in a study with rats, the diuresis induced by THC in mice also is weakly naturetic compared to furosemide and further investigations in this area may yield a new, clinically beneficial diuretic.

In contrast, our data suggest that development of peripherally selective cannabinoid CB1 agonists may be beneficial for patients suffering from bladder dysfunction.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872476/

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Diuretic effects of cannabinoids.

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“These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms.

Overall, our data indicate that diuresis is a CB1-mediated effect that may serve as a reliable and objective physiologic measure of cannabinoid action in rats; the circumstances under which these results represent a potential therapeutic benefit or potential liability of cannabinoids remain to be determined.

The implications of these findings currently are poorly understood, although a better understanding of mechanisms and sites of action by which cannabinoids increase urine loss may lead to the rational development of novel cannabinergic medications.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533417/

“Diuretics are medicines that help reduce the amount of water in the body. Diuretics are used to treat the buildup of excess fluid in the body that occurs with some medical conditions such ascongestive heart failure, liver disease, and kidney disease. Some diuretics are also prescribed to treat high bloodpressure. These drugs act on the kidneys to increase urine output. This reduces the amount of fluid in the bloodstream,which in turn lowers blood pressure.” http://medical-dictionary.thefreedictionary.com/diuretics
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AM251 Suppresses Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells.

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“Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the causative mechanisms of kidney fibrosis.

In our study, we screened lipophilic compounds using a lipid library including approximately 200 lipids to identify those that suppressed EMT induced by a transforming growth factor (TGF)-β1 stimulus.

Our findings regarding the effects of AM251 on the TGF-β signaling pathway may inform development of a novel therapeutic agent suppressing EMT, thus preventing kidney fibrosis.”

https://www.ncbi.nlm.nih.gov/pubmed/27936102

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Cannabinoid receptors in the kidney.

“The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis.

CB1 and CB2 have been reported to play key roles in renal function and dysfunction. Recent studies have determined that antagonism of CB1 and agonism of CB2 in diabetic nephropathy and obesity associated kidney disease can reduce albuminuria, potentially by acting on both the glomeruli and tubules. Emerging studies have also identified a role for CB1 in renal diseases associated with fibrosis, with CB1 upregulated in multiple models of human nephropathies.

Emerging studies using isolated cells, rodent models, and human studies have identified a critical role for the endocannabinoid system in renal function and disease. Thus, therapeutics that modulate the activity of CB1 and CB2 in renal disease could become clinically relevant.”

http://www.ncbi.nlm.nih.gov/pubmed/27367912

 

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