Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats

Abstract

The renal reabsorption of glucose is mediated by two major classes of transporters. Initially, luminal glucose is concentrated in tubules by Na(+)-glucose cotransporters (Na(+)-GLUT). Afterwards, glucose reaches the blood space through facilitative glucose transporters, low-Michaelis constant (Km) GLUT1 and high-Km GLUT2. Hence, the transtubular flux of glucose could be impaired in hyperglycemia because the outwardly directed glucose gradient, from tubule to blood, is potentially lowered. However, in diabetic rats, transtubular glucose flux is not reduced but increased. In this work the molecular mechanism underlying this adaptation was examined. We tested the hypothesis that upregulation of renal tubular high-Km GLUT2 gene may compensate for the decrease in the tubule to blood glucose gradient. In rat tubules, GLUT1 protein and mRNA steady-state levels were reduced, and GLUT2 protein and mRNA levels were increased in rats after 2, 3, and 4 wk of uncontrolled streptozotocin-induced diabetes. These molecular adaptations were associated with augmented facilitative glucose flux. In summary, changes in GLUT1 and GLUT2 gene expression are important to the preservation of renal glucose reabsorption in hyperglycemia.

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

“…Therefore, since GLUT5 is considered to be a fructose transporter in vivo, with only a low affinity for glucose [25], and GLUT1 protein levels in the renal tubule are generally considered to be reduced [26,27] or unchanged in diabetes [9], it is reasonable to hypothesise that GLUT2 might be responsible for glucose-induced tubular cell hypertrophy in diabetes. Indeed, two indirect findings also suggest a potential pathophysiological link between GLUT2 function and the kidney: one is the finding of renal hypertrophy and glomerulopathy in patients with GLUT2 mutations in the Fanconi-Bickel syndrome [28]; the other is the recent observation that flavonoids, which are known to ameliorate the changes of diabetic nephropathy in experimental models [29], inhibit GLUT2 production [30].…”

Streptozotocin diabetes and the expression of GLUT1 at the brush border and basolateral membranes of intestinal enterocytes

“…The effects of diabetes on enterocyte expression of GLUT1 have not previously been studied, presumably because of the reported absence of this protein in enterocytes from non-diabetic animals [8]. GLUT1 is, however, expressed in Caco-2 cells, a colonic cell line which displays enterocyte-like properties [7].…”

“…Although the protein is found in certain transporting cells e.g. renal proximal tubule and Caco-2 cells [6,7], there is, to date, no evidence for its expression in normal small intestinal epithelium [8]. In the present study we have used confocal immunofluorescence microscopy of rat jejunum, together with Western blotting of BBM and BLM prepared from intestinal mucosa, in order to examine the normal enterocyte distribution of *Corresponding author.…”

Reduced cortical renal GLUT1 expression induced by angiotensin-converting enzyme inhibition in diabetic spontaneously hypertensive rats

“…In the early S1 segment, where the bulk of filtered glucose is reabsorbed, the low affinity/ high capacity glucose transporters, SGLT2 and GLUT2 are co-expressed in the luminal brush border membrane and in the basolateral membrane, respectively. Increases in the cortical GLUT2 gene expression have been extensively reported in diabetes (9)(10)(11)(12)(13)(14)(15), and are important for renal glucose reabsorption maintenance in this condition, since high blood and interstitial glucose concentrations may lower the outwardly directed glucose gradient from tubule to blood (11). GLUT1 protein is also detected in the outer renal cortex, where it is not related to the tubule epithelial cells, but to the mesangial cells (16).…”