MO076: GLUT2 as a Key Factor in the Pathogenesis of Diabetic Kidney Disease

Abstract

Abstract BACKGROUND AND AIMS Diabetic kidney disease (DKD) affects more than 30% of all diabetic patients. It is strongly associated with increased morbidity, mortality and global healthcare burden. Furthermore, it is considered the primary cause of end-stage kidney disease (ESKD). The renal proximal tubular cells (RPTCs) are highly susceptible to diabetes-induced hyperglycaemia, and glucose handling in these cells plays a central role in the pathophysiology of DKD; yet, the molecular mechanisms underlying hyperglycaemia-induced tubulopathy are poorly understood. Although glucose transporter 2 (GLUT2) is a major glucose transporter in the RPTCs, its exclusive role and the underlying mechanism by which it contributes to the pathogenesis of DKD are poorly known. Here, we reveal its fundamental role in the pathogenesis of DKD. METHOD By using the Cre-lox technique, we developed a novel mouse strain with reduced GLUT2 expression specifically in the RPTCs and crossed it with the Akita-diabetic mouse strain to generate diabetic RPTC-GLUT2-/- mice. We evaluated the renal phenotype of the null mice and compared it with their diabetic wild-type (WT) littermate controls by assessing renal patho-morphological changes, measuring blood and urine biochemical alterations, and testing renal function by qPCR, immunohistochemistry and ELISAs. Moreover, we measured glucose uptake by the kidney in the diabetic RPTC-GLUT2-/- mice and their WT controls by utilizing µPET-MRI imaging of tail vein-injected 18[F]-deoxy-D-glucose (FDG). RESULTS Whereas no significant changes were found in the weight or the diabetic status of the null mice in comparison with the WT animals, considerable improvements of renal function in the diabetic RPTC-GLUT2-/- mice were measured. These positive changes included significant reductions in urine creatinine, albuminuria, albumin-to-creatinine ratio (ACR) and urinary kidney injury marker 1 (KIM-1) levels. Interestingly, the hyperglycemia-induced patho-morphological changes in the kidney as well as renal injury, fibrosis and inflammation were significantly attenuated in the diabetic RPTC-GLUT2-/- mice. Moreover, the renal uptake of 18[F]-FDG was significantly decreased in the diabetic RPTC-GLUT2-/- mice compared with their WT littermate controls. CONCLUSION Fundamental novel observations regarding the contribution of GLUT2 in RPTCs to the development and pathogenesis of DKD have emerged. Our findings 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 patho-morphology. Correspondingly, our results indicate that GLUT2-linked molecular mechanisms greatly affect DKD pathophysiology. Therefore, studying these cellular pathways have a major potential for therapeutic intervention of DKD and other kidney diseases.