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

J Am Soc Nephrol. 2018 Feb;29(2):434-448. doi: 10.1681/ASN.2017040371. Epub 2017 Oct 13.


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.

Keywords: CB1 Receptor; Endocannabinoids; GLUT2; Renal Proximal Tubule Cells; diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / urine
  • Animals
  • Biological Transport
  • Blood Glucose / metabolism
  • Blood Urea Nitrogen
  • Creatinine / urine
  • Diabetic Nephropathies / chemically induced
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism*
  • Dogs
  • Fibrosis
  • Glucose / metabolism
  • Glucose Transporter Type 2 / antagonists & inhibitors
  • Glucose Transporter Type 2 / genetics*
  • Glucose Transporter Type 2 / metabolism*
  • Insulin / blood
  • Islets of Langerhans / pathology
  • Kidney Tubules, Proximal / pathology*
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Mice, Knockout
  • Protein Kinase C beta / metabolism
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Streptozocin
  • Sulfonamides / pharmacology


  • 3-(4-chlorophenyl)-N-methyl-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine
  • Blood Glucose
  • CNR1 protein, mouse
  • Glucose Transporter Type 2
  • Insulin
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Slc2a2 protein, mouse
  • Sulfonamides
  • Streptozocin
  • Creatinine
  • Protein Kinase C beta
  • JD5037
  • Glucose