Early development of podocyte injury independently of hyperglycemia and elevations in arterial pressure in nondiabetic obese Dahl SS leptin receptor mutant rats.

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 wk of age, body weight was 35% higher in the SSLepRmutant strain compared with SSWT rats and remained elevated throughout the entire study. The SSLepRmutant strain exhibited impaired glucose tolerance and increased plasma insulin levels at 6 wk 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 to 10 wk of age. However, by 18 wk of age, the development of hypertension was more severe in the SSLepRmutant strain compared with SSWT rats (201 ± 10 vs. 155 ± 3 mmHg, respectively). Interestingly, proteinuria was substantially higher at 6 wk of age in the SSLepRmutant strain vs. 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 compared with SSWT rats as early as 6 wk of age. By 18 wk of age, plasma creatinine levels were twofold higher in the SSLepRmutant strain vs. SSWT rats, suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SSLepRmutant strain develops podocyte injury and proteinuria independently of hyperglycemia and elevated arterial pressure that later progresses to CKD.