Abstract
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.
Highlights
Diabetes mellitus, a chronic disease that is reaching epidemic proportions,[1] has been described as a catalyst for a number of conditions, one of which is diabetic nephropathy (DN)
Our results indicate that diabetesinduced upregulation in renal glucose transporter 2 (GLUT2) expression and dynamics can be mitigated by peripheral blockade or genetic ablation of cannabinoid-1 receptor (CB1R) in renal proximal tubule cell (RPTC) to reduce glucose reabsorption and prevent the development of DN
The effect of high glucose levels on [Ca2+]i was significantly intogether, these findings suggest that blocking CB1R has the potential to inhibit the trafficking of glucose through RPTCs by affecting GLUT2 expression and ameliorating the hibited in a calcium-free medium (Figure 3E), suggesting that tubular cell damage occurred during diabetes. the glucose-induced rise in [Ca2+]i is largely due to increased calcium entry into the cell, with a smaller proportion generated by the release of calcium from intracellular stores
Summary
A chronic disease that is reaching epidemic proportions,[1] has been described as a catalyst for a number of conditions, one of which is diabetic nephropathy (DN). Endocannabinoids (eCBs), acting via the cannabinoid-1 receptor (CB1R), mediate the deleterious consequences of DN.[17,18,19,20,21,22] The renal expression of CB1R is enhanced in diabetic mice,[18,22] and its genetic/pharmacologic activation increases proteinuria and podocyte dysfunction,[23] whereas its chronic blockade improves renal function.[18,20,24,25,26] Because a concern over adverse neuropsychiatric effects[27] limits the therapeutic potential of globally acting CB1R antagonists,[28] peripherally restricted blockers have been recently developed and preclinically tested.[29,30,31,32,33]. Our results indicate that diabetesinduced upregulation in renal GLUT2 expression and dynamics can be mitigated by peripheral blockade or genetic ablation of CB1R in RPTCs to reduce glucose reabsorption and prevent the development of DN
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