Podocytes are key cells in the glomerular filtration barrier with a major role in the development of diabetic nephropathy. Podocytes are insulin-sensitive cells and have a functionally active local renin-angiotensin system. The presence and activity of angiotensin-converting enzyme 2 (ACE2), the main role of which is cleaving pro-fibrotic and pro-inflammatory angiotensin-II into angiotensin-(1-7), has been demonstrated in podocytes. Conditionally immortalized mouse podocytes were cultured with insulin in the presence and absence of albumin. We found that insulin increases ACE2 gene and protein expression, by real-time PCR and western blot respectively, and enzymatic activity within the podocyte and these increases were maintained over time. Furthermore, insulin favored an "anti-angiotensin-II" regarding ACE/ACE2 gene expression balance and decreased fibronectin gene expression as a marker of fibrosis in the podocytes, all studied by real-time PCR. Likewise insulin incubation seemed to protect podocyte from cell death, studied by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. However, all these effects disappeared in the presence of albumin, which may mimic albuminuria, a main feature in DN pathophysiology. Our results suggest that modulation of renin-angiotensin system balance, fibrosis and apoptosis by insulin in the podocyte may be an important factor in preventing the development and progression of diabetic kidney disease but the presence of albuminuria seems to block these beneficial effects.