We previously showed that long term consumption of soy protein diet (SoyP) reduces renal damage in obese Zucker (ObeseZ) rats by restoring urinary NO₂ and NO₃ excretion (UNO₂/NO₃V), suggesting that nitric oxide deficiency may contribute to the renal progression observed in this model. In addition, there is compelling evidence that hiperleptinemia produced deleterious effects on the kidney through its interaction with the short leptin receptor (Ob-Ra). This study was designed to evaluate the contribution of the NO/eNOS system, renal oxidative stress, and Ob-Ra expression to the renoprotection conferred by the consumption of a SoyP in ObeseZ rats. Ten lean and 10 male ObeseZ rats were included. One half of each group was fed with a 20% SoyP and the other half with a 20% casein protein diet (CasP) over the course of 160 days. eNOS protein levels and phosphorylation, renal lipoperoxidation (rLPO), and antioxidant enzyme activity and mRNA levels were assessed. In addition, renal Ob-Ra, TGF-, and kidney injury molecule (Kim-1) mRNA levels, as well as urinary Kim-1 levels, were measured. Renal injury observed in ObeseZ rats fed with CasP was not associated with changes in eNOS expression or phosphorylation. However, this group did present with increased rLPO, reduced catalase activity, and up-regulation of Ob-Ra, TGF-1 and Kim-1. In contrast, ObeseZ rats fed with a SoyP exhibited a reduction in p-eNOS Thr495 phosphorylation and renal lipoperoxidation, as well as an enhanced catalase activity. These findings were associated with a significant reduction of Ob-Ra, TGF-1, and Kim-1 mRNA levels and urinary Kim-1 protein. Our results show that renoprotection by SoyP in ObeseZ rats is in part mediated by increased NO availability secondary to a reduction in eNOS-T495 phosphorylation and oxidative stress, together with a significant reduction in Ob-Ra and TGF-1 expression.