title: Induction of proteinuria by cannabinoid receptors 1 signaling activation in CB1 transgenic mice.
abstract: Proteinuria is not only a sign of kidney damage but is also involved in the progression of renal disease as an independent pathologic factor. Although patients with mutated type 1 cannabinoid receptors (CB1) polymorphism are associated with renal microvascular damage, the biologic role of CB1 signaling in proteinuria remains uncharacterized till now. Herein, we investigate whether CB1 participates in glomerular proteinuria in CB1 transgenic mice and treatment with CB1 agonist WIN55212-2 rat, neither of which are diabetic models. The CB1 transgenic mice and rats treated with CB1 agonist WIN55212-2 had higher kidney weight and urinary protein concentrations but not blood glucose levels compared with the wild-type group. A combination of laser-capture microsdissection, quantitative reverse transcription-polymerase chain reaction, immunoblotting and immunohistochemical validation revealed that CB1 transgenic mice and rats treated with CB1 agonist WIN55212-2 had higher vascular endothelial growth factor (VEGF) expression in renal glomeruli than that of the wild-type group. Geneticorpharmacological activation of CB1 by transgenic CB1 mice or treatment with WIN55212-2 reduced nephrin expression in the renal glomeruli compared with that of the wild-type group in the glomerular mesanglium. Taken together, CB1 transgenic mice and rats treated with CB1 agonist WIN55212-2 induced proteinuria with upregulation of CB1 resulting in impaired nephrin expression, by inducing excess VEGF reaction in the renal glomeruli. Genetic and pharmacological manipulation of CB1 signaling revealed VEGF-dependent nephrin depression of glomerulopathy. Controlling CB1 activity can be used an alternative strategy for sustaining renal function in the presence of CB1 activation.
authors.affiliation: Department of Nephrology (Y-CH, C-CL, Y-HS, C-LL), and Kidney and Diabetic Complications Research Team (Y-CH, C-CL, Y-HS, C-LL), Chang Gung Memorial Hospital, Chiayi, Taiwan; Kidney Research Center (C-LL), Chang Gung Memorial Hospital, Taipei, Taiwan; College of Medicine (C-LL), Chang Gung University College of Medicine, Taoyuan, Taiwan; and Chronic Kidney Disease Care Center (Y-CH, C-CL, Y-HS, C-LL), Division of Endocrinology and Metabolism (CH), Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yung-Chien
authors.initials: YC
authors.lastname: Hsu
authors.forename: Chen-Chou
authors.initials: CC
authors.lastname: Lei
authors.forename: Ya-Hsueh
authors.initials: YH
authors.lastname: Shih
authors.forename: Cheng
authors.initials: C
authors.lastname: Ho
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Lin
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000009:adverse effects / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000009:adverse effects / Q000494:pharmacology; D009281:Naphthalenes / Q000009:adverse effects / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D011507:Proteinuria / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D001786:Blood Glucose; D008565:Membrane Proteins; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone