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Induction of proteinuria by cannabinoid receptors 1 signaling activation in CB1 transgenic mice
Yung-Chien Hsu1, Chen-Chou Lei, Ya-Hsueh Shih
1Department 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.
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.
Insights
Cannabinoid receptor 1 (CB1) activation in mice and rats increases proteinuria by upregulating vascular endothelial growth factor (VEGF) and reducing nephrin expression, highlighting a new therapeutic target for kidney disease.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Proteinuria signifies kidney damage and independently drives renal disease progression.
- The role of cannabinoid receptor 1 (CB1) signaling in proteinuria is currently uncharacterized.
- CB1 receptor gene mutations are linked to renal microvascular damage.
Purpose of the Study:
- To investigate the role of CB1 signaling in glomerular proteinuria.
- To determine if CB1 activation induces proteinuria in non-diabetic models.
- To elucidate the molecular mechanisms underlying CB1-mediated proteinuria.
Main Methods:
- Utilized CB1 transgenic mice and rats treated with the CB1 agonist WIN55212-2.
- Employed laser-capture microdissection, quantitative RT-PCR, immunoblotting, and immunohistochemistry.
- Assessed kidney weight, urinary protein concentration, blood glucose, VEGF, and nephrin expression.
Main Results:
- CB1 activation led to increased kidney weight and proteinuria without affecting blood glucose.
- VEGF expression was significantly upregulated in the renal glomeruli of CB1-activated mice and rats.
- Nephrin expression in the renal glomeruli was reduced following CB1 activation.
Conclusions:
- CB1 activation induces proteinuria by upregulating VEGF and downregulating nephrin expression in the renal glomeruli.
- VEGF-dependent nephrin depression contributes to glomerulopathy.
- Modulating CB1 signaling presents a potential strategy for preserving renal function.
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