Cannabinoid receptor type 2 promotes kidney fibrosis through orchestrating β-catenin signaling

Abstract

The endocannabinoid system has multiple effects. Through interacting with cannabinoid receptor type 1 and type 2, this system can greatly affect disease progression. Previously, we showed that activated cannabinoid receptor type 2 (CB2) mediated kidney fibrosis. However, the underlying mechanisms remain underdetermined. Here, we report that CB2 was upregulated predominantly in kidney tubular epithelial cells in unilateral urinary obstruction and ischemia-reperfusion injury models in mice, and in patients with a variety of kidney diseases. CB2 expression was closely correlated with the progression of kidney fibrosis and accompanied by the activation of β-catenin. Furthermore, CB2 induced the formation of a β-arrestin 1/Src/β-catenin complex, which further triggered the nuclear translocation of β-catenin and caused fibrotic injury. Incubation with XL-001, an inverse agonist to CB2, or knockdown of β-arrestin 1 inhibited CB2-triggered activation of β-catenin and fibrotic injury. Notably, CB2 potentiated Wnt1-induced β-arrestin 1/β-catenin activation and augmented the pathogenesis of kidney fibrosis in mice with unilateral ischemia-reperfusion injury or folic acid-induced nephropathy. Knockdown of β-arrestin 1 inhibited the CB2 agonist AM1241-induced β-catenin activation and kidney fibrosis. By promoter sequence analysis, putative transcription factor binding sites for T-cell factor/lymphoid enhancer factor were found in the promoter regions of the CB2 gene regardless of the species. Overexpression of β-catenin induced the binding of T-cell factor/lymphoid enhancer factor-1 to these sites, promoted the expression of CB2, β-arrestin 1, and the proto-oncogene Src, and triggered their accumulation. Thus, the CB2/β-catenin pathway appears to create a reciprocal activation feedback loop that plays a central role in the pathogenesis of kidney fibrosis. The endocannabinoid system has multiple effects. Through interacting with cannabinoid receptor type 1 and type 2, this system can greatly affect disease progression. Previously, we showed that activated cannabinoid receptor type 2 (CB2) mediated kidney fibrosis. However, the underlying mechanisms remain underdetermined. Here, we report that CB2 was upregulated predominantly in kidney tubular epithelial cells in unilateral urinary obstruction and ischemia-reperfusion injury models in mice, and in patients with a variety of kidney diseases. CB2 expression was closely correlated with the progression of kidney fibrosis and accompanied by the activation of β-catenin. Furthermore, CB2 induced the formation of a β-arrestin 1/Src/β-catenin complex, which further triggered the nuclear translocation of β-catenin and caused fibrotic injury. Incubation with XL-001, an inverse agonist to CB2, or knockdown of β-arrestin 1 inhibited CB2-triggered activation of β-catenin and fibrotic injury. Notably, CB2 potentiated Wnt1-induced β-arrestin 1/β-catenin activation and augmented the pathogenesis of kidney fibrosis in mice with unilateral ischemia-reperfusion injury or folic acid-induced nephropathy. Knockdown of β-arrestin 1 inhibited the CB2 agonist AM1241-induced β-catenin activation and kidney fibrosis. By promoter sequence analysis, putative transcription factor binding sites for T-cell factor/lymphoid enhancer factor were found in the promoter regions of the CB2 gene regardless of the species. Overexpression of β-catenin induced the binding of T-cell factor/lymphoid enhancer factor-1 to these sites, promoted the expression of CB2, β-arrestin 1, and the proto-oncogene Src, and triggered their accumulation. Thus, the CB2/β-catenin pathway appears to create a reciprocal activation feedback loop that plays a central role in the pathogenesis of kidney fibrosis. Translational StatementCannabinoid receptors are involved in tissue fibrosis. Although cannabinoid receptor type 1 activation has been reported to mediate renal fibrosis, the role of cannabinoid receptor type 2 (CB2) remains to be demonstrated in detail. This study provides evidence for the detrimental role of CB2 in the pathogenesis of renal fibrosis. The findings highlight a novel CB2/β-catenin pathway that promotes renal fibrosis. Blockade of CB2 is a potential therapeutic intervention to prevent renal fibrosis in a variety of nephropathies. The findings also provide health warnings to the fast-growing group of exocannabinoid consumers, for both recreational and medicinal purposes. Cannabinoid receptors are involved in tissue fibrosis. Although cannabinoid receptor type 1 activation has been reported to mediate renal fibrosis, the role of cannabinoid receptor type 2 (CB2) remains to be demonstrated in detail. This study provides evidence for the detrimental role of CB2 in the pathogenesis of renal fibrosis. The findings highlight a novel CB2/β-catenin pathway that promotes renal fibrosis. Blockade of CB2 is a potential therapeutic intervention to prevent renal fibrosis in a variety of nephropathies. The findings also provide health warnings to the fast-growing group of exocannabinoid consumers, for both recreational and medicinal purposes. The endocannabinoid system plays a critical role in cardiovascular, neurodegenerative, and metabolic diseases.1Huang H.C. Wang S.S. Hsin I.F. et al.Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats.Hepatology. 2012; 56: 248-258Crossref PubMed Scopus (54) Google Scholar, 2Schmole A.C. Lundt R. Toporowski G. et al.Cannabinoid receptor 2-deficiency ameliorates disease symptoms in a mouse model with Alzheimer’s disease-like pathology.J Alzheimers Dis. 2018; 64: 379-392Crossref PubMed Scopus (15) Google Scholar, 3Barutta F. Grimaldi S. Franco I. et al.Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice.Kidney Int. 2014; 86: 979-990Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 4Liu J. Godlewski G. Jourdan T. et al.Cannabinoid-1 receptor antagonism improves glycemic control and increases energy expenditure through sirtuin-1/mechanistic target of rapamycin complex 2 and 5’Adenosine monophosphate-activated protein kinase signaling.Hepatology. 2019; 69: 1535-1548Crossref PubMed Scopus (16) Google Scholar Through interacting with cannabinoid receptors type 1 (CB1) and type 2 (CB2),5Ruiz de Azua I. Lutz B. Multiple endocannabinoid-mediated mechanisms in the regulation of energy homeostasis in brain and peripheral tissues.Cell Mol Life Sci. 2019; 76: 1341-1363Crossref PubMed Scopus (34) Google Scholar the endocannabinoid system could also affect the prognosis of kidney diseases.6Barutta F. Bruno G. Mastrocola R. et al.The role of cannabinoid signaling in acute and chronic kidney diseases.Kidney Int. 2018; 94: 252-258Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar CB1 plays a detrimental role in renal fibrosis.7Lecru L. Desterke C. Grassin-Delyle S. et al.Cannabinoid receptor 1 is a major mediator of renal fibrosis.Kidney Int. 2015; 88: 72-84Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 8Udi S. Hinden L. Earley B. et al.Proximal tubular cannabinoid-1 receptor regulates obesity-induced CKD.J Am Soc Nephrol. 2017; 28: 3518-3532Crossref PubMed Scopus (56) Google Scholar, 9Hinden L. Udi S. Drori A. et al.Modulation of renal GLUT2 by the cannabinoid-1 receptor: implications for the treatment of diabetic nephropathy.J Am Soc Nephrol. 2018; 29: 434-448Crossref PubMed Scopus (40) Google Scholar However, the role of CB2 in renal fibrosis remains elusive. CB2 was previously reported to be involved in the immune system.10Barutta F. Grimaldi S. Gambino R. et al.Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.Nephrol Dial Transplant. 2017; 32: 1655-1665Crossref PubMed Scopus (33) Google Scholar Recently, CB2 was found to be expressed in kidneys.3Barutta F. Grimaldi S. Franco I. et al.Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice.Kidney Int. 2014; 86: 979-990Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar,11Zhou L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar, G. A. I. et of cannabinoid receptors in Google Scholar, et and of in the of the PubMed Scopus Google Scholar diabetic and CB2 plays a role in F. Grimaldi S. Franco I. et al.Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice.Kidney Int. 2014; 86: 979-990Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar However, in fibrotic CB2 is upregulated in tubular cells and involved in reported in L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar CB2 is also expressed in and and their L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar the of the of CB2, are also in L. Desterke C. Grassin-Delyle S. et al.Cannabinoid receptor 1 is a major mediator of renal fibrosis.Kidney Int. 2015; 88: 72-84Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Although a study that the activation of CB2 by renal L. Desterke C. Grassin-Delyle S. et al.Cannabinoid receptor 1 is a major mediator of renal fibrosis.Kidney Int. 2015; 88: 72-84Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar a CB2 and a with to CB2 CB1 reduce renal fibrotic L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar which the role of CB2 in renal fibrosis. evidence in has that CB2 and A. Cannabinoid receptor type 2 (CB2) formation in Full Text Full Text PDF PubMed Scopus Google T. et al.Cannabinoid CB2 receptor and PubMed Scopus Google Scholar However, CB2 renal fibrosis is receptors the of a role in and immune signaling and the and of 2017; 28: Full Text Full Text PDF PubMed Scopus Google T. of in the immune 2019; PubMed Scopus Google Scholar are to receptors and PubMed Scopus Google Scholar J. F. in the 2018; PubMed Scopus Google J. receptor therapeutic in the 2019; PubMed Scopus Google Scholar and A. et of the and improves in Alzheimer’s disease mouse 2015; PubMed Scopus (40) Google Scholar type receptor receptor type and receptor type also central in kidney J. et receptor type plays a role in 2017; PubMed Scopus Google Scholar, S. L. et activation and renal Am Soc Nephrol. 2014; PubMed Scopus Google Scholar, J. et promotes in renal 2017; PubMed Scopus Google Scholar The activation of the receptor and of the for receptor and of 1 and 2 in signaling and of the cannabinoid receptor 1 Full Text Full Text PDF PubMed Scopus Google C. The multiple of cannabinoid 1 receptor PubMed Scopus Google Scholar in C. The multiple of cannabinoid 1 receptor PubMed Scopus Google Scholar β-arrestin 1 is for of protein kinase and the proto-oncogene of 1 and 2 in signaling and of the cannabinoid receptor 1 Full Text Full Text PDF PubMed Scopus Google C. C. et signaling cannabinoid 2 2017; 28: PubMed Scopus (15) Google et factor receptor regulates through 2019; PubMed Scopus (16) Google Scholar is a of the kinase to the activation of J. S. in chronic kidney 2017; PubMed Scopus (33) Google Scholar Notably, CB2 to the of and is activated by the of C. C. et signaling cannabinoid 2 2017; 28: PubMed Scopus (15) Google Scholar However, their in renal tubular injury remain a β-catenin is in is in a variety of J. J. J. et signaling renal fibrosis and is with 2019; PubMed Scopus Google L. et to injury and Int. 2019; Full Text Full Text PDF PubMed Scopus (56) Google Scholar Through binding to the T-cell factor/lymphoid enhancer binding factor to target β-catenin signaling is with renal tubular and fibrotic C. Zhou S. Zhou et promotes renal fibrosis by in tubular epithelial Am Soc Nephrol. 2018; 29: PubMed Scopus Google Scholar, L. signaling and system in chronic kidney PubMed Scopus Google Scholar, L. et is a urinary and mediator of kidney Am Soc Nephrol. 2017; 28: PubMed Scopus Google Scholar is that the of or of to the activation of T. G. The and of J. 2012; PubMed Scopus Google Scholar a potential and β-catenin However, the are this we the role of β-catenin in CB2 signaling in chronic kidney disease tubular injury in and in and the in the CB2/β-catenin CB2 expression was by in in CB2 expression was upregulated ischemia-reperfusion injury a which acute kidney injury β-catenin is L. Zhou et activation of signaling to Am Soc Nephrol. PubMed Scopus Google Scholar and predominantly in renal tubular was by The of was with the progression of disease and was correlated with the of CB2 and Furthermore, the CB2 was also correlated with the expression of a of tubular injury the expression of and which are L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar expression were the expression of kidney injury a of tubular was upregulated in a and for CB2 with tubular a of a of and a of CB2 was with and tubular was in the the of CB2 with tubular injury and fibrosis in unilateral obstruction in and the of CB2 was correlated with renal fibrosis and Furthermore, for CB2 and in mice also that CB2 is to the progression of The of the in for CB2 in mouse and models was also with a CB2 and in CB2 mice a a control β-catenin the progression of acute kidney injury to and plays a role in renal L. signaling and system in chronic kidney PubMed Scopus Google L. Zhou et activation of signaling to Am Soc Nephrol. PubMed Scopus Google Scholar we further the CB2 and β-catenin with CB2, we the expression of β-catenin and and the 2 of renal L. et to injury and Int. 2019; Full Text Full Text PDF PubMed Scopus (56) Google L. signaling and system in chronic kidney PubMed Scopus Google L. et is a urinary and mediator of kidney Am Soc Nephrol. 2017; 28: PubMed Scopus Google Scholar were upregulated in mice Furthermore, the expression of CB2 was correlated with β-catenin and target and for β-catenin and CB2 was predominantly in the renal tubular with expression of β-catenin also CB2 and β-catenin expression kidney of with and in with the in CB2 expression was greatly in of the patients and with β-catenin in tubular and were also The of CB2 was in CB2 mice kidney tubular a tubular epithelial were with a L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar in induced the nuclear translocation of an of L. et to injury and Int. 2019; Full Text Full Text PDF PubMed Scopus (56) Google Scholar expression of induced the of and which were further upregulated with and Overexpression of CB2 induced the of β-catenin and and and triggered the in the and Furthermore, induced increases of the were further by with a CB2 expression was was by cells were with with a that gene J. J. J. et signaling renal fibrosis and is with 2019; PubMed Scopus Google C. Zhou S. Zhou et promotes renal fibrosis by in tubular epithelial Am Soc Nephrol. 2018; 29: PubMed Scopus Google Scholar in AM1241-induced of that β-catenin plays a critical role in CB2 cells were with in the or of XL-001, a novel inverse agonist of CB2 in L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar in triggered the of β-arrestin 1 and to with the formation of a Furthermore, induced the binding of β-arrestin 1 with which to sites, an of β-catenin induced nuclear translocation of both β-catenin and β-arrestin 1 This is with a report that β-arrestin 1 a protein to β-catenin signaling activation in L. R. P. et is a nuclear of 32: PubMed Scopus Google Scholar their in the and nuclear the in β-arrestin 1 and β-catenin were in the treatment with of inhibited both the and nuclear of β-arrestin 1 and β-catenin expression of CB2 induced the of the of and was further by with β-arrestin knockdown of β-arrestin 1 β-catenin and greatly inhibited of and were expression was by an role of β-arrestin in β-catenin in mice were with expression expression or both CB2 and expression through gene an approach that is to in and J. J. J. et signaling renal fibrosis and is with 2019; PubMed Scopus Google L. et to injury and Int. 2019; Full Text Full Text PDF PubMed Scopus (56) Google Scholar CB2 expression was by and in and renal fibrotic in and expression of CB2 or in of CB2 and in kidney and fibrosis, that CB2 and the of kidney fibrosis. of CB2 and induced an in in or mice in expression of CB2 or induced the of and of CB2 and further these effects. were and were by in expression of CB2 or induced the of β-arrestin 1 and an of J. S. in chronic kidney 2017; PubMed Scopus (33) Google Scholar The expression of β-arrestin 1 and were further by of CB2 and for CB2 with β-catenin by in and in mice with of CB2 and tubular cells expressed the potential role of β-catenin in the CB2 pathway the expression of β-arrestin 1 and β-catenin by in CB2 with to their Furthermore, in mice, or Wnt1-induced activation of β-catenin and and were further by with The expression of by and analysis, also demonstrated that CB2 a Wnt1-induced tubular injury and The experimental is in in and in folic expression of CB2 or induced the of CB2, and CB2 were further by of CB2 and the expression of β-arrestin 1 and in CB2 and expression of both β-arrestin 1 and Furthermore, of β-catenin showed that CB2 or the activation of and a were the expression of β-catenin and and were by The of and were upregulated by expression of CB2 or and further by their and and were and were further that CB2 plays an role in the β-arrestin β-catenin cannabinoid receptor type 2 (CB2) and renal fibrosis in folic nephropathy. and renal and expression in in a the control the treatment group the group the group renal expression of kidney injury and in of this the of this the role of in of β-arrestin 1 in mice with The of β-arrestin 1 was by of further and knockdown of β-arrestin 1 inhibited these increases in mice and The of showed that knockdown of β-arrestin 1 greatly AM1241-induced tubular injury The showed that knockdown of β-arrestin 1 inhibited β-catenin expression Furthermore, the of and further the role of with β-arrestin 1 in kidney were the expression of or was by we that β-arrestin 1 knockdown inhibited CB2 an activation loop CB2, β-arrestin 1, and β-catenin and and of the fibrotic further demonstrated β-arrestin 1 inhibited renal fibrosis and were multiple of putative T-cell factor enhancer binding factor binding sites in the promoter regions of both and mouse CB2 cells were with activated β-catenin expression L. S. et of the system are novel of Am Soc Nephrol. 2015; PubMed Scopus Google Scholar showed that of β-catenin promoted T-cell factor or enhancer binding factor-1 binding to the T-cell factor/lymphoid enhancer binding factor binding sites of the CB2 gene promoter regions and of CB2 and protein and the of β-catenin β-catenin further triggered the formation of a complex with CB2 inhibited expression of β-arrestin 1 and activation of CB2 that the CB2/β-catenin pathway appears to create a reciprocal activation feedback loop that plays an role in the pathogenesis of renal fibrosis The of is and the for renal disease is P. The of chronic kidney and Nephrol. 2017; PubMed Scopus Google Scholar However, are therapeutic in the of and are also involved in T. T. Zhou R. in and Sci. 2018; Full Text Full Text PDF PubMed Scopus (22) Google Scholar, I. G. T. et in 2014; PubMed Scopus Google Scholar, J. et receptor promotes in mice through and 64: Full Text Full Text PDF PubMed Scopus Google Scholar, C. of in 2017; PubMed Scopus Google Scholar kidney been therapeutic J. et receptor type plays a role in 2017; PubMed Scopus Google Scholar, S. L. et activation and renal Am Soc Nephrol. 2014; PubMed Scopus Google Scholar, J. et promotes in renal 2017; PubMed Scopus Google J. et activation of renal acute kidney Full Text Full Text PDF PubMed Scopus Google Scholar Notably, β-arrestin 1 and of S. L. et activation and renal Am Soc Nephrol. 2014; PubMed Scopus Google Scholar could the of an to kidney L. S. et of the system are novel of Am Soc Nephrol. 2015; PubMed Scopus Google Scholar However, has been reported that is a CB2 and β-catenin. CB2 is a of the de Azua I. Lutz B. Multiple endocannabinoid-mediated mechanisms in the regulation of energy homeostasis in brain and peripheral tissues.Cell Mol Life Sci. 2019; 76: 1341-1363Crossref PubMed Scopus (34) Google Scholar previously found that CB2 is expressed in tubular and L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar CB2 is also expressed in and F. Grimaldi S. Franco I. et al.Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice.Kidney Int. 2014; 86: 979-990Abstract Full Text Full Text PDF PubMed Scopus (39) Google et and of in the of the PubMed Scopus Google Scholar The role of CB2 in was in the the of CB2 and in was previously reported that a CB2 agonist could renal fibrosis.7Lecru L. Desterke C. Grassin-Delyle S. et al.Cannabinoid receptor 1 is a major mediator of renal fibrosis.Kidney Int. 2015; 88: 72-84Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar a role of CB2 in renal fibrosis through and with the CB2 inverse agonist XL-001, a novel CB2 inverse agonist that the binding to the CB2 with the the CB1 receptor and a of L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar β-catenin and are by or inhibition of L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar that CB2 is a of the CB2 could β-catenin. However, this to be this we showed that CB2 β-catenin activation through a study also the role of the endocannabinoid system in renal fibrosis. the 2 has a for has a for CB1 and CB2 for CB1 is P. R. signaling through cannabinoid 2 receptors of a PubMed Scopus Google Scholar is the endocannabinoid agonist for the CB2 of in the central system the CB2 PubMed Scopus Google Scholar Notably, the kidney of and C. et and of the in the renal 2012; PubMed Scopus Google are in fibrosis of the accompanied by the in which in the activation of both CB2 and L. Desterke C. Grassin-Delyle S. et al.Cannabinoid receptor 1 is a major mediator of renal fibrosis.Kidney Int. 2015; 88: 72-84Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar the detrimental role of CB2 in the pathogenesis of renal fibrosis was demonstrated by in L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar and is further in the Although a report showed that CB2 is expressed by both cells and a F. F. S. et role of cannabinoid receptor type 2 in a mouse model of diabetic PubMed Scopus Google Scholar CB2 and are upregulated and L. Desterke C. Grassin-Delyle S. et al.Cannabinoid receptor 1 is a major mediator of renal fibrosis.Kidney Int. 2015; 88: 72-84Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar,11Zhou L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google Scholar Notably, in renal fibrosis of mice and a variety of CB2 is predominantly expressed in renal tubular in and that the of CB2 is a in the fibrotic we in of CB2 to expression of The that CB2 is expressed in tubular The this in the of the in in the of and the for CB2 in the also the tubular receptor and C. The multiple of cannabinoid 1 receptor PubMed Scopus Google C. C. et signaling cannabinoid 2 2017; 28: PubMed Scopus (15) Google Scholar The of the in was with a CB2 and both were in CB2 mice we formation of CB2 with CB1 in and tubular cells that their be However, CB1 expression was by or XL-001, which further to the previously the of CB2 and be to their an the of the and findings that of CB2 is a potential therapeutic intervention to prevent renal fibrosis. with patients with findings provide health warnings to the fast-growing group of exocannabinoid consumers, for both recreational and medicinal F. and the in health and 2017; PubMed Scopus Google Scholar could to the activation of both CB1 and CB2 which kidney Although a report showed that β-arrestin 1 plays a role in renal fibrosis and activation of J. et ameliorates renal fibrosis by signaling in Mol 2018; PubMed Scopus Google Scholar we further the functional mechanisms of the β-arrestin CB2/β-catenin pathway in detail. found β-arrestin 1 is β-arrestin 2 in mice is that β-arrestin 1 is for activation and Src, protein kinase and of 1 and 2 in signaling and of the cannabinoid receptor 1 Full Text Full Text PDF PubMed Scopus Google C. C. et signaling cannabinoid 2 2017; 28: PubMed Scopus (15) Google et factor receptor regulates through 2019; PubMed Scopus (16) Google Scholar that activation of could mediate factor receptor and and of transcription J. S. in chronic kidney 2017; PubMed Scopus (33) Google Scholar we could the that these are also the of that β-catenin signaling is mediated by β-arrestin β-arrestin 1 is a and a protein to the activation of β-catenin by to the novel is that CB2 is a target of β-catenin. of β-catenin been previously reported by L. et is a urinary and mediator of kidney Am Soc Nephrol. 2017; 28: PubMed Scopus Google L. S. et of the system are novel of Am Soc Nephrol. 2015; PubMed Scopus Google Scholar CB2 was in this is that the CB2/β-catenin pathway appears to create a reciprocal activation loop that promotes the pathogenesis of renal fibrosis. that expressed CB2 is involved in renal fibrosis through β-arrestin β-catenin β-catenin the expression of CB2, which receptor activation and of the a novel CB2/β-catenin pathway that promotes renal fibrosis and that inhibition of CB2 or β-arrestin 1 fibrosis through inhibition of the reciprocal activation the mice were the of the were by for the and The model was by the with an the the were for and the kidney was 1 the folic mice were with folic a of expression of or CB2 or knockdown of β-arrestin 1 in mice was by a gene L. Zhou S. Yang P. et al.Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.Kidney Int. 2018; 94: Full Text Full Text PDF PubMed Scopus Google T. G. The and of J. 2012; PubMed Scopus Google Scholar The experimental are in and The were by the of the CB2 mice in were CB2 receptor was by kidney were renal the and the control were kidney of patients renal The kidney were with and were by the and the tubular epithelial cells were by C. and were with a and were by an CB2 were were with and by of CB2 a kidney were and to and The were a L. R. P. et is a nuclear of 32: PubMed Scopus Google Scholar and were in and are in the expression was by The was by previously C. C. et signaling cannabinoid 2 2017; 28: PubMed Scopus (15) Google Scholar are in the was a system was an The of the in are in the cells were with the CB2 expression and with expression or The was a system were and the was a The and are in the the are expressed of the was were by for of 2 or of by the or for of 2 of was was and the This was by of of and and and the of of with and and Scholar of and and a of with

Topics & Concepts