Reduced Expression of Glucose Transporter 2 (GLUT2) in the Renal Proximal Tubular Cells (RPTCs) Attenuates Diabetic Kidney Disease (DKD)
2The Wohl Institute for Translational Medicine, Hadassah Hebrew University Medical Center
3The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center
4Center for Integrative Genomics, University of Lausanne
DKD affects more than 30% of all diabetic patients. It is strongly associated with global healthcare burden and is considered the primary cause of end-stage kidney disease (ESKD). Glucose handling in the RPTCs plays a central role in DKD pathophysiology; yet, the molecular mechanisms underlying hyperglycemia-induced tubulopathy are poorly understood. Although GLUT2 is a major glucose transporter in the RPTCs, its exclusive role and contribution to DKD are unknown. Here, we reveal its fundamental role in the pathogenesis of DKD.
By using the Cre-lox technique, we developed a novel mouse strain with reduced RPTC-GLUT2 expression, and crossed it with the Akita-diabetic mouse strain, generating diabetic RPTC-GLUT2-/- mice. We evaluated the renal phenotype of the RPTC-GLUT2-/- mice compared to their WT controls. We assessed renal patho-morphology, blood and urine biochemistry, and tubulointerstitial fibrosis and inflammation. Moreover, we measured renal glucose uptake by μPET-MRI imaging.
Whereas no significant changes were found in the weight and diabetic status of the RPTC-GLUT2-/- mice compared to their WT controls, considerable improvements of renal function in the diabetic RPTC-GLUT2-/- mice were measured, including significantly reduced urine creatinine, albuminuria, ACR, and KIM-1 levels. Interestingly, the hyperglycemia-induced pathomorphological changes in the kidney, as well as renal injury, fibrosis, and inflammation, were significantly attenuated in the diabetic RPTC-GLUT2-/- mice. Moreover, the renal glucose uptake was significantly decreased due to the reduced RPTC-GLUT2-/- expression.
Our novel observations suggest that RPTC-GLUT2 not only affects glucose reabsorption but also modulates cellular function, eventually affecting the degree of renal inflammation, tubulointerstitial fibrosis, diabetic kidney injury, and renal pathomorphology. Correspondingly, our results indicate that GLUT2-linked molecular mechanisms greatly affect DKD pathophysiology.
