Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly up-regulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild type mice. Obese wild type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated TGF-β signaling and renal fibrosis. In contrast, obese TSP1 deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-β 1, fibronectin and collagen type IV in mesangial cells isolated from wild type mice. These leptin stimulated effects were abolished in TSP1 deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity or hyperleptinemia induced kidney dysfunction.