Endothelial function in proteinuric renal disease

Nephrotic-range proteinuria is associated with a several-fold increase risk of cardiovascular infarction. This increased risk is accompanied by endoth elial dysfunction, which is not related to increased blood pressure and is not correctable by acute administration of L-arginine. The latter is in dir ect contrast to what has been found in patients with primary hypercholester olemia, suggesting that either hypoalbuminemia itself or other aspects of t he dyslipidemia characteristic of the nephrotic syndrome impair endothelial function. Lysophosphatidylcholine (lyso-PC) is formed during oxidative mod ification of cholesterol, and lyse-PC in oxidized low-density lipoprotein ( LDL) is responsible for reduced endothelial function in vitro. However, in the circulation, lyse-PC is tightly bound to albumin. Indeed, the addition of albumin can restore endothelial function: which was previously disturbed by lyse-PC. Hypoalbuminemia induces a shift in lyse-PC to lipoproteins, no tably LDL, and to erythrocytes. The latter directly induces a reduction in deformability that can also be corrected by the addition of albumin. Hypoal buminemia may disturb endothelial function, either by directly affecting G( i)-protein-dependent signal transduction or indirectly by changing the conf iguration of the cell membrane. Such a change in cell membrane configuratio n will disturb binding of ligands to receptors and of endothelial nitric ox ide (NO) synthase to caveolin. However, other pathways have been suggested, such as stimulation by lyse-PC of vasoconstriction mediated by protein kin ase C. It remains to be shown whether lipid-lowering and antiproteinuric st rategies have independent positive effects on endothelial function in nephr otic subjects.