Urea induces macrophage proliferation by inhibition of inducible nitric oxide synthesis

Background. Atherosclerosis is a major cause of morbidity and mortality in chronic renal failure and is associated with the proliferation of macrophag es within atherosclerotic lesions. Methods. Because the progression of atherosclerosis as a consequence of dec reased nitric oxide synthesis has been described, we investigated the corre lation between the inhibition of inducible nitric oxide synthase (iNOS) by urea, macrophage proliferation as assayed by cell counting, tritiated thymi dine incorporation and measurement of cell protein, and macrophage apoptosi s. Results. Urea induces a dose-dependent inhibition of inducible nitric oxide synthesis in lipopolysaccharide-stimulated mouse macrophages (RAW 264.7) w ith concomitant macrophage proliferation. Macrophage proliferation, as dete rmined by cell counting, became statistically significant at 60 mM urea, co rresponding to a blood urea nitrogen level of 180 mg/100 mi, concentrations seen in uremic patients, iNOS protein expression showed a dose-dependent r eduction, as revealed by immunoblotting when cells were incubated with incr easing amounts of urea. The decrease of cytosolic DNA fragments in stimulat ed macrophages incubated with urea shows that the proliferative actions of urea are associated with a decrease of NO-induced apoptosis. Conclusions. Our data demonstrate that the inhibition of iNOS-dependent NO production caused by urea enhances macrophage proliferation as a consequenc e of diminished NO-mediated apoptosis.