Overview of glucose signaling in mesangial cells in diabetic nephropathy.

Clinical studies such as the Diabetes Control and Complications Trial (DCCT) in subjects with type 1 diabetes (1), the UK Prospective Diabetes Study (UKPDS) in subjects with type 2 diabetes (2), and the Kumamoto Study in Japanese subjects with type 2 diabetes (3) clearly link longstanding hyperglycemia to diabetic nephropathy. Furthermore, the regression of glomerular pathologic changes by the maintenance of normoglycemia for 10 yr was shown in eight subjects with type 1 diabetes who were treated with pancreas transplantation (4). Therefore, the understanding of the hyperglycemia-related molecular pathogenesis of diabetic nephropathy is truly needed to provide further insight into therapeutic strategies for diabetic nephropathy. Diabetic nephropathy is characterized histologically by an accumulation of extracellular matrix (ECM) proteins in the glomerular mesangium (5). Functionally, an increase in GFR, glomerular hyperfiltration, found in the early phase of diabetes has been proposed to be related to the future development of diabetic nephropathy (6,7). These abnormalities could be caused by functional changes in diabetic glomeruli, particularly in glomerular mesangial cells because mesangial cells were found to be capable of producing ECM proteins (8,9) and regulating GFR through their contractility (10,11). An enhancement of the production of type IV collagen and fibronectin (12–14), a reduction of the contractile responsiveness to angiotensin II (15–17), and an overproduction of vasorelaxing eicosanoids (18–20) have been shown in diabetic glomeruli and mesangial cells cultured under high-glucose conditions. These functional changes in glomeruli and mesangial cells in diabetes are considered to be caused by the metabolic abnormalities in glomeruli and mesangial cells specific to diabetes. In this review, we would like to describe glucose-induced signaling abnormalities that lead to functional disturbances of mesangial cells in the diabetic milieu. Glucose Transport into Mesangial Cells The first step of glucose signaling is the transport of glucose into the cells through specific glucose transporters. Previous studies indicate that mesangial cells express only a small amount of insulin receptors or insulin-sensitive facilitative glucose transporters (GLUT-4). Alternatively, mesangial cells were found to express two types of glucose transporters, facilitative and sodium-coupled transporters (21), and brain type glucose transporter (GLUT-1) was shown to be a predominant isoform (22,23). Therefore, excessive extracellular glucose in the diabetic milieu will easily enter the cells through GLUT-1 in an insulin-independent manner and induce various signaling pathways. The importance of GLUT-1 was suggested by the overexpression of GLUT-1 in mesangial cells, in which an excessive production of ECM proteins was observed even under normal glucose conditions (24,25). Furthermore, glucose-induced fibronectin production was found to be reduced by antisense GLUT-1 in mesangial cells (26). We have found that transforming growth factor1 (TGF1), one of the cytokines playing an important role in the development of diabetic nephropathy, is able to stimulate glucose uptake in mesangial cells by inducing the expression of mRNA and protein of GLUT1 (27). Our results also indicate that endogenous TGF1 produced by mesangial cells under high-glucose conditions stimulates glucose uptake and thus may accelerate glucose-induced metabolic abnormalities in mesangial cells.