Glucose is a key fuel and an important metabolic substrate in mammals. Renal proximal tubular cells (PTCs) not only reabsorb filtered glucose but are also believed to play a role in the glucotoxicity associated with renal pathogenesis, such as in diabetes. The proximal tubule environment is where 90% of the filtered glucose is reabsorbed by the low-affinity/high-capacity Na(+)/glucose cotransporter 2 (SGLT2) and facilitated diffusion glucose transporter 2 (GLUT2). Both active and facilitative glucose transporters have distinct distribution profiles along the proximal tubule related to their particular kinetic characteristics. A number of mechanisms contribute to the changes in the cellular functions, which occur in response to exposure to various endogenous factors. Hyperglycemia was reported to regulate the renal SGLT activities through the reactive oxygen species-nuclear factor-kappaB pathways, which suggests that the transcellular glucose uptake within the PTCs contribute to the development of diabetic-like nephropathy. Angiotensin II (ANG II) plays an important role in its development through epidermal growth factor receptor (EGFR) transactivation. Therefore, a combination of high glucose, ANG II, and EGF are involved in diabetic-like nephropathy by regulating the SGLT activity. In addition, endogenously enhanced SGLTs have a cytoprotective function. The renal proximal tubules play a major role in regulating the plasma glucose levels, and there is increasing interest in the renal glucose transporters on account of their potential implications in the treatment of various conditions including diabetes mellitus.

GLUT2-mediated uptake provides a low-affinity, highcapacity route for glucose to enter proximal tubule cells during hyperglycemia and might therefore initiate the changes in cellular carbohydrate metabolism that have been linked to diabetic nephropathy. It is noteworthy that the Fanconi-Bickel syndrome, which is associated with glycogen accumulation in proximal tubule cells and a diabetic-like nephropathy, has been linked to mutations of the GLUT2 gene. 4 The emerging importance of GLUT2 in proximal tubule physiology suggests that expression of the transporter should be a major focus when considering the implications of chronic hyperglycemia for tubular damage.