Glucose transporters in diabetic nephropathy

Abstract

Changes in glucose transporter expression in glomerular cells occur early in diabetes. These changes, especially the GLUT1 increase in mesangial cells, appear to play a pathogenic role in the development of ECM expansion and perhaps other features of diabetic nephropathy. In addition, it appears that at least some diabetic patients may be predisposed to nephropathy because of polymorphisms in their GLUT1 genes. GLUT1 overexpression leads to increased glucose metabolic flux which in turn triggers the polyol pathway and activation of PKC alpha and B1. Activation of these PKC isoforms can lead directly to AP-1 induced increases in fibronectin expression and ECM accumulation. Other, more novel effects of GLUT1 on cellular hypertrophy and injury could also promote changes of diabetic nephropathy. Strategies to prevent GLUT1 overexpression could ameliorate or prevent the progression of diabetic nephropathy.

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

“…Recent studies have described the involvement of PKC and calcium-dependent signalling pathways in the control of facilitative glucose transport in mesangial cells and intestinal enterocytes [1,6,18]. In the present study, incubation of proximal tubules for 30 min with 1 μmol/l PMA, a PKC agonist, had no effect on the V max or the K t (control: 505±54 vs PMA: 462±18 μmol/l) of SGLT-mediated glucose transport (Fig.…”

“…Most studies have concentrated on the effect of high glucose concentrations on mesangial cells, since glomerulopathy is the most characteristic clinical and histological feature of diabetic renal disease. These studies have provided convincing evidence that overproduction of GLUT1 and protein kinase C (PKC)-βI are linked to glucose-induced mesangial cell damage and extracellular matrix deposition [1,2]. Diabetes also increases renal size, mainly due to proximal tubular cell hypertrophy and thickening of the tubular cell basement membrane [3], leading to eventual tubular cell loss and declining renal function [4]; however, the underlying mechanisms affecting proximal tubular cell function and their relationship to glucose transport have not been studied in any detail.…”

“…Data from clinical trials and experimental models of diabetes have shown a strong correlation between hyperglycaemia and the development and progression of diabetic nephropathy [1]. Most studies have concentrated on the effect of high glucose concentrations on mesangial cells, since glomerulopathy is the most characteristic clinical and histological feature of diabetic renal disease.…”

“…Since GLUT1 and PKC-βl may influence mesangial cell size in diabetes [1], and also due to the fact that PKC-βII regulates GLUT2 protein levels at the enterocyte BBM, we investigated the relationship between changes in circulating glucose concentration and protein levels of PKC-βI, PKC-βII and other PKC isoforms, together with GLUT2 abundance at the proximal tubule BBM. In order to study as wide a range of glucose concentrations as possible, we used normal animals and STZ-diabetic animals, with or without prior treatment with low or high doses of nicotinamide.…”

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.…”