The accelerated non-enzymatic modification of
proteins by Maillard reaction during prolonged
hyperglycemia is a key player in the diabetes associated pathology. In addition,
hypoxia has been implicated in the recent past as a modulating factor. Therefore we have examined the interaction of glycation modified
human serum albumin (
AGE-HSA) and
deferoxamine (DFO) mimicked
hypoxia on the expression of
hypoxia inducible factor 1α (HIF-1α), and the role of RAGE (receptor for AGE) signaling in up-regulation of HIF-1α. Expression of
VEGF (a downstream target of HIF-1α) and sICAM-1 (inflammatory marker) was also detected. When HUVEC were subjected to
hypoxia, highest expression of HIF-1α was observed. When treated with
AGE-HSA at two concentrations, higher expression was found vis-a-vis control, with 0.2 mg ml(-1) than 2.0 mg ml(-1) which was mediated in part by RAGE as determined by RAGE silencing. However, when the cells were exposed to a combination treatment of
hypoxia and
AGE-HSA, a biphasic effect at the two different concentrations was observed as compared to the individual treatments.
VEGF was synergistically up-regulated by
hypoxia and
AGE-HSA. On the other hand sICAM-1 was up-regulated by
AGE-HSA but down-regulated by
hypoxia. These results show that
AGE-HSA functions as a non-hypoxic factor which modulates the expression of HIF-1α in a concentration dependent manner in the range studied. It can be concluded that
glycated serum proteins may activate HIF-1α independently in diabetes. Further, when both
glycated proteins and hypoxic conditions are present, they act in opposition in regulation of HIF-1α.