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

Autor: Gil Leibowitz, Matan Geron, Adi Drori, Yael Riahi, Yaakov Nahmias, Saja Baraghithy, Joseph Tam, Rivka Hadar, Anna Permyakova, Alina Nemirovski, Liad Hinden, Sabina Tsytkin-Kirschenzweig, Merav Cohen, Shiran Udi, Asaad Gammal, Avi Priel
Rok vydání: 2017
Předmět:
0301 basic medicine
Blood Glucose
Male
Cannabinoid receptor
Pharmacology
Blood Urea Nitrogen
Madin Darby Canine Kidney Cells
Diabetic nephropathy
Kidney Tubules
Proximal
Mice
0302 clinical medicine
Receptor
Cannabinoid
CB1
Insulin
Diabetic Nephropathies
Receptor
Glucose Transporter Type 2
Mice
Knockout
Sulfonamides
biology
General Medicine
3. Good health
Renal glucose reabsorption
Nephrology
030220 oncology & carcinogenesis
Creatinine
medicine.symptom
endocrine system
Inflammation
digestive system
Streptozocin
03 medical and health sciences
Islets of Langerhans
Dogs
Diabetes mellitus
Protein Kinase C beta
medicine
Albuminuria
Animals
business.industry
Biological Transport
medicine.disease
Fibrosis
030104 developmental biology
Basic Research
Glucose
Tubulointerstitial fibrosis
biology.protein
GLUT2
Pyrazoles
business
Zdroj: Journal of the American Society of Nephrology
ISSN: 1046-6673
DOI: 10.1681/ASN.2017040371
Popis: Altered glucose reabsorptionviathe 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.
Databáze: OpenAIRE
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