Lipid abnormalities and activation of the local renin angiotensin system (RAS) may be involved in the pathogenesis of chronic glomerular disease. This study investigated whether low-density lipoprotein (LDL) activates local RAS in cultured human mesangial cells (HMC) and, at the same time, whether angiotensin II (Ang II) mediates LDL-induced mesangial cell proliferation and superoxide (O₂^-) generation. Quiescent HMC were exposed to 50 to 200 µg/ml of LDL or 10^-7 to 10^-10 M Ang II for 0.5 to 24 hours in the presence or absence of 10^-6 M losartan, an Ang II type 1 (AT1) receptor antagonist, or 10^-5 M diphehylendieodonium (DPI) or 10^-4 M apocynin, inhibitors of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase. LDL induced an up to 3-fold increase in the Ang II levels in the culture medium of HMC. LDL upregulated AT1 receptor and angiotensinogen mRNA expression in HMC. LDL incubated with HMC increased O₂^- production by up to 3.3 times compared to the level of control cells. The LDL-induced increased O₂^- generation was suppressed by losartan, DPI or apocynin. LDL significantly increased mesangial [³H]-thymidine or [³H]-leucine incorporation, while these processes were abrogated by losartan. In conclusion, LDL increases Ang II production by mesangial cells, which in turn results in increased O₂^- production and cell proliferation and hypertrophy, these effects of Ang II being mediated by the AT1 receptor.