Renal expression and localization of the facilitative glucose transporters GLUT1 and GLUT12 in animal models of hypertension and diabetic nephropathy

Abstract

Renal tubular glucose reabsorption is mediated by facilitative glucose transporter (GLUT) proteins and energy-dependent sodium glucose luminal transporters. Glucose transport in the diabetic kidney is upregulated and has been implicated in the pathogenesis of progressive diabetic nephropathy. Hyperglycemia, hypertension, and activation of the renin-angiotensin system are believed important in the development of the disease. The present study examines the renal expression of the facilitative glucose transporters GLUT1 and GLUT12 in rat models of diabetic nephropathy. Sprague-Dawley and transgenic (mRen-2)27 rats received either streptozotocin-induced diabetes or vehicle. GLUT12 expression and localization were determined by immunohistochemistry, immunoblotting, in situ hybridization, and confocal immunofluorescence. GLUT1 immunolabeling was detected on the basolateral membrane throughout the nephron. GLUT12 was localized to the distal tubules and collecting ducts. A significant increase in GLUT12 immunolabeling was measured in Ren-2 controls and Ren-2 diabetic animals compared with Sprague-Dawley controls. GLUT12 expression was higher in Ren-2 diabetic compared with Sprague-Dawley diabetic rats. Long-term diabetes resulted in significant increases in GLUT1 levels in the renal proximal tubules and expression was higher in Ren-2 diabetic than Sprague-Dawley diabetic rats. GLUT12 protein was localized to the cytoplasm and to the apical membrane of human and rat distal tubules and collecting ducts. The apical localization of GLUT12 in the distal tubules and collecting ducts suggests that it could contribute to additional glucose reabsorption in the late nephron. Levels of both GLUT1 and GLUT12 are elevated in animal models of hypertension and diabetic nephropathy.

The facilitative glucose transporter GLUT12: what do we know and what would we like to know?

“…However, neither total nor cell-surface GLUT12 protein content was affected in any adipose depot in the IR animals [39]. In a Ren-2 rat model of diabetic nephropathy, GLUT12 overexpression was described in distal tubules and collecting ducts compared to control animals, suggesting that GLUT12 could be involved in the regulation of glucose reabsorption in distal renal tubules in response to elevated glucose levels [15]. Further analysis of GLUT12 cellular location and targeting in the MDCK cell line demonstrated apical targeting of GLUT12 from the perinuclear location, in response to elevated glucose concentration, in which mTOR signalling pathway was involved.…”

“…Its mRNA is abundant in skeletal muscle, heart and prostate, and it is present at low levels in brain and kidney [30]. In rat, expression of GLUT12 protein has been described during foetal development in skeletal muscle, brown adipose tissue, heart, foetal chondrocytes, lung, kidney [18], mammary gland during pregnancy [19] and kidney distal tubes and collecting ducts [15]. In cow, its mRNA expression is abundant in spleen and skeletal muscle, less expressed in kidney, testis and mammary gland, and even lower expressed in liver, lung and intestine [24].…”

“…During the past years, research has focused on the study of GLUT12 role as a secondary insulin sensitive transporter [26,32] and its role on impaired insulin signalling pathologies [15,38,39]. Its expression in some tumour tissues has been described [5,29,35] and recently it has been proposed as one of the key proteins in the glucose supply to malignant cells [48] (Figure 5).…”

Roles of facilitative glucose transporter GLUT1 in [18F]FDG positron emission tomography (PET) imaging of human diseases

“…Glucose transport in the diabetic kidney is upregulated and has been implicated in the pathogenesis of progressive diabetic nephropathy [372]. Hyperglycemia, hypertension and activation of the reninangiotensin system are thought to be important in the development of the disease and expression levels of GLUT1 are elevated under conditions of hypertension and diabetic nephropathy [373,374].…”

Diabetic threesome (hyperglycaemia, renal function and nutrition) and advanced glycation end products: evidence for the multiple-hit agent?

“…If the cell cannot efficiently down regulate insulin-independent glucose intake in hyperglycaemia it becomes overloaded, which has been convincingly shown for endothelial (9,10) , mesangial (11) and renal tubular (12) cells, all of which are targets for vascular damage by hyperglycaemia in diabetes.…”