Our results showed a natriuretic effect with leptin treatment for 7 days, which was normalized in the leptin plus losartan group and is in concordance with the observed enhanced urinary flow rate. Our results also indicated that the natriuretic effect might be due to tubular mechanisms because the Na+ filtration load and Na+ plasma levels are similar in the groups studied. However, the natriuretic effect was absent in the 28-day group. This indicates that the enhanced Na+ excretion in the 7-day group could be an effort to counterbalance the increase in the SBP, but this effect is blunted in the 28-day group. In fact, both the increases in renal sympathetic nerve activity and the activation of the RAS contribute to the modulation of the pressure natriuresis mechanism and impairs the ability of the kidneys to maintain blood pressure and sodium homeostasis. The increase in the plasma Ang II levels observed in the 28-day leptin-treated rats further support these results. Considering that short leptin receptors are expressed in the glomerulus, that long leptin receptors are expressed in the medulla, and that we did not observe differences in leptin receptors mRNA expression after chronic treatment, we next investigated whether leptin treatment induces renal morphological changes. The peptide induced a significant increase in the MLN4924 glomerular area, namely glomerular hypertrophy, which worsened from 7 to 28 days of treatment. Treatment with leptin plus losartan decreased the hypertrophy, suggesting that Ang II via the AT1 ONX-0914 receptor is at least partially responsible for this effect. Glomerular hypertrophy is considered a relevant event in the progression of glomerular injury. The rats treated with leptin for 7 and 28 days exhibited enhanced desmin staining, which is an important marker of glomerular lesion and is associated with the observed hypertrophy. In normal rats, desmin is expressed mainly in mesangial cells. Desmin expression in podocytes occurs after injury; therefore, desmin staining can be used as a reliable marker of podocyte damage. The albuminuria observed in the rats treated with leptin further confirms the leptin��s effects on glomerular injury. The histological analysis also demonstrated that leptin treatment for 28 days induced interstitial damage, observed as an increase in the fractional interstitial area, which was normalized in the leptin plus losartan group. Moreover, the rats treated with leptin for 28 days showed a significant infiltration of macrophages in the renal tissue, which was confirmed by ED-1 staining, that indicates a local inflammatory process and corroborates with the interstitial damage. The infiltration of ED-1 positive cells was reduced in the leptin plus losartan group, which indicates the protective effect of the antagonism of the AT1 receptor. The positive effects of leptin on the mRNA expression of fibrotic and inflammatory components are in agreement with the results presented so far.