Leptin is a peptide hormone that is mainly, but not exclusively, produced in adipose tissue and plays a pivotal role in regulating food intake and energy expenditure. Besides its effects on regulation of body weight, appetite and energy expenditure, leptin exhibits influence on the immune system and may contribute to the deterioration of renal function. These direct and indirect renal effects of leptin could partly explain obesity-associated kidney disease and may be also relevant for diabetic nephropathy in type 2 diabetes. Leptin is primarily metabolized in the kidney, presumably by binding to megalin, a multiligand receptor in the proximal tubule, tubular uptake and endocytosis. The kidney expresses abundant concentrations of the small isoform of the leptin receptor (Ob-Ra). In cultured renal rat endothelial cells and mesangial cells obtained from db/db mice, leptin can signal through the Ob-Ra receptor isoform. The peptide stimulates proliferation of glomerular endothelial cells, increases TGF-beta1 synthesis, and collagen type IV production. In contrast, leptin did not influence TGF-beta1 production in mesangial cells, but the peptide stimulates glucose transport in these cells, increased collagen type I synthesis, and lead to an upregulation of surface TGF-beta type II receptors through signal transduction pathways involving phosphatidylinositol-3-kinase. Leptin also stimulates hypertrophy, but not proliferation in cultured rat mesangial cells. Infusion of leptin for 3 weeks into normal rats fosters development of glomerulosclerosis and proteinuria. In addition, transgenic mice with leptin overexpression demonstrated a increase in collagen type IV and fibronectin mRNA in the kidney. Additional previously described direct and indirect effects of leptin on the kidney include natriuretic effects, an increase in sympathetic nervous activity, and stimulation of reactive oxygen species. These findings collectively suggest that the kidney is a target organ for leptin and that this hormone might play an important role in renal pathophysiology.