Urea-induced ROS caused endothelial dysfunction in chronic renal failure

Abstract

The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood [2] .Here we investigate the hypothesis that concen- trations of urea associated with CRF and increased ROS production in adipocytes3 might also increase ROS production directly in arterial endothelial cells, causing the same pathophysi- ologic changes seen with hyperglycemia [1]. For these purpose, confluent primary human aor- tic endothelial cells (HAECs) were incubated with either 20mM urea or with 20mM mannitol used as osmotic control, for 48 hours. Urea induces mitochondrial reactive oxygen species in HAEC and cause pro-inflammatory changes in endothelial cells. Breafly, PGI2 Synthase activ- ity, NFκB p65 and NFκB-specific target genes mRNA expression (MCP-1 and VCAM-1 ) [3] and their protein levels were evaluated. Moreover, we have shown that urea-induced ROS produc- tion increases PKC activity, hexosamine pathway activity and intracellular AGE formation in HAEC. In addition, urea-induced ROS decrease GAPDH activity, increase DNA strand breaks and increase PARP activity in HAEC. In summary, urea increases mitochondrial ROS produc- tion in arterial endothelial cells, thereby activating pro-atherosclerotic pathways and directly inactivating PGI2 synthase, a critical endothelial-specific antiatherosclerotic enzyme in vitro. The present findings provide further insight into the underlying mechanisms that contribute to the enhanced cardiovascular risk associated with chronic renal failure.