Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

Abstract

Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR) γ agonists are used increasingly in the treatment of type 2 diabetes. In the context of renal disease, PPARγ agonists reduce microalbuminuria in diabetic nephropathy; however, the mechanisms underlying this effect are unknown. Glomerular podocytes are newly characterised insulin-sensitive cells and there is good evidence that they are targeted in diabetic nephropathy. In this study we investigated the functional and molecular effects of the PPARγ agonist rosiglitazone on human podocytes. Methods Conditionally immortalised human podocytes were cultured with rosiglitazone and functional effects were measured with glucose-uptake assays. The effect of rosiglitazone on glucose uptake was also measured in 3T3-L1 adipocytes, nephrin-deficient podocytes, human glomerular endothelial cells, proximal tubular cells and podocytes treated with the NEFA palmitate. The role of the glucose transporter GLUT1 was investigated with immunofluorescence and small interfering RNA knockdown and the plasma membrane expression of GLUT1 was determined with bis-mannose photolabelling. Results Rosiglitazone significantly increased glucose uptake in wild-type podocytes and this was associated with translocation of GLUT1 to the plasma membrane. This effect was blocked with GLUT1 small interfering RNA. Nephrin-deficient podocytes, glomerular endothelial cells and proximal tubular cells did not increase glucose uptake in response to either insulin or rosiglitazone. Furthermore, rosiglitazone significantly increased basal and insulinstimulated glucose uptake when podocytes were treated with the NEFA palmitate. Conclusions/interpretation In conclusion, rosiglitazone has a direct and protective effect on glucose uptake in wild-type human podocytes. This represents a novel mechanism by which PPARγ agonists may improve podocyte function in diabetic nephropathy.

Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes

“…Our study is the first to show that the increased expression of SHP-1 triggers insulin unresponsiveness in renal podocytes. Interestingly, with the use of an insulin-resistant type 2 diabetes model, previous data have reported that free fatty acids cause profound modifications in cultured podocytes, including decreased IR-␤, IRS-1, and Akt expression (20). By contrast, our results did not show any significant changes in IR␤, IRS1, or IRS2 expression in podocytes or renal cortex of Ins2 ϩ/C96Y mice.…”

“…However, podocytes react similarly to insulinstimulated glucose uptake kinetics and glucose transport (GLUT-1 and GLUT-4) expression as skeletal muscle and adipocytes (6). Furthermore, some evidence also suggested that rosiglitazone, a peroxisome proliferator-activated receptor-␥ agonist, enhances GLUT-1 translocation in podocytes, increasing insulin sensitivity (20), and protects podocytes from injury (19). Although insulin has been shown to be essential for normal glomerular filtration, relatively little is known about cellular actions of insulin in podocytes.…”

Comparison of Direct Action of Thiazolidinediones and Glucocorticoids on Renal Podocytes: Protection from Injury and Molecular Effects

“…Together, our findings suggest that Pio and Rosi may have potential clinical utility as either a primary or adjunctive therapy for NS or other diseases treated with GCs. Moreover, these findings may also lend new mechanistic insight into the well established but poorly understood renal protective effects of TZDs in diabetic nephropathy (Lennon et al, 2009).…”

ACE2 deficiency shifts energy metabolism towards glucose utilization

“…PPAR-γ agonists improve glucose control in patients with T2DM, which is partly attributable to their insulin sensitizing effects [25]. PPAR-γ activation also increases glucose uptake by translocating GLUT-1 to the plasma membrane [26]. It is possible that this 3 -RER, skeletal muscle NEFA oxidation and gene expression.…”