This study investigates whether angiotensin converting enzyme (ACE) inhibitors can block high glucose-induced increase of angiotensin II (Ang II) levels in cultured rat mesangial cells. Incubation of cells with high glucose for 5 days increased Ang II in the cell media (extracellular) and cell lysates (intracellular) by similar to 1.5-fold and similar to 2.2-fold, respectively. Captopril blocked high glucose-induced increase in extracellular Ang II levels but not in intracellular Ang II levels. Since the inability of captopril to inhibit intracellular Ang II in intact cells could be explained by failure of the drug to enter the cells, further studies were performed using lysates from cells pre-treated with high glucose for 5 days. Addition of captopril to cell lysates was indeed able to inhibit Ang I conversion to Ang II but only partially. These findings suggest the involvement of non-ACE mechanisms in Ang II formation from Ang I in mesangial cells. Published by Elsevier Inc.