Role of Sodium Glucose Transporter in High Glucose Mediated Angiotensin Type 1 receptor Down‐regulation in Human Proximal Tubule Cells

Abstract

Previously, we have characterized the human angiotensin type 1 receptor (hAT1) promoter architecture for high glucose (HG) mediated transcriptional repression in human proximal tubule epithelial cells (hPTEC). In the present study, we investigated the role of glucose transporters in HG mediated hAT1 repression. Primary hPTEC were exposed to 5.5 mM normal glucose (NG) or 25 mM HG, and changes in receptor expression and glucose transporter activity were determined. Exposure of cells to HG resulted in down‐regulation of angiotensin II specific binding (4034 to 1360 dpm/well) and hAT1 mRNA expression (58.0 % of normal) at 48 h. Under similar conditions, we observed significant increases in glucose uptake (influx) in HG treated cells that were concentration and time dependent. In NG treated cells, inhibiting the sodium glucose transporters (SGLTs) with phloridzin and facilitative glucose transporters (GLUTs) with phloretin decreased glucose influx by 28.8 and 45.5 %, respectively. In contrast, in HG treated cells inhibiting the SGLTs decreased glucose influx by 52.0 %, however GLUT mediated glucose uptake remained the same. Pretreatment of cells with SGLT inhibitor reversed HG mediated down‐regulation of hAT1. Our study shows for the first time that in hPTEC HG mediated hAT1 down‐regulation is largely mediated through SGLT dependent glucose influx pathway.