The current study examined the effect of obesity on the development of renal injury within the genetic background of the Dahl salt-sensitive rat with a dysfunctional leptin receptor derived from Zinc-finger nucleases (SSLepRmutant strain). At 6 weeks of age, body weight was 35% higher in the SSLepRmutant strain compared to SSWT rats and remained elevated throughout the entire study. The SSLepRmutant strain exhibited impaired glucose tolerance and increased plasma insulin levels at 6 weeks of age suggesting insulin resistance while SSWT rats did not. However, blood glucose levels were normal throughout the course of the study. Systolic arterial pressure (SAP) was similar between the two strains from 6-10 weeks of age. However, by 18 weeks of age, the development of hypertension was more severe in the SSLepRmutant strain compared to SSWT rats (201±10 vs. 155±3 mmHg, respectively). Interestingly, proteinuria was substantially higher at 6 weeks of age in the SSLepRmutant strain versus SSWT rats (241±27 vs. 24±2 mg/day, respectively) and remained elevated until the end of the study. The kidneys from the SSLepRmutant strain displayed significant glomerular injury including podocyte foot process effacement and lipid droplets when compared to SSWT rats as early as 6 weeks of age. By 18 weeks of age, plasma creatinine levels were 2-fold higher in the SSLepRmutant strain versus SSWT rats suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SSLepRmutant strain develops podocyte injury and proteinuria independent of hyperglycemia and elevated arterial pressure that later progresses to CKD.