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

Abstract

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 (SS LepR mutant strain). At 6 wk of age, body weight was 35% higher in the SS LepR mutant strain compared with SS WT rats and remained elevated throughout the entire study. The SS LepR mutant strain exhibited impaired glucose tolerance and increased plasma insulin levels at 6 wk of age, suggesting insulin resistance while SS WT 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 SS LepR mutant strain compared with SS WT rats (201 ± 10 vs. 155 ± 3 mmHg, respectively). Interestingly, proteinuria was substantially higher at 6 wk of age in the SS LepR mutant strain vs. SS WT rats (241 ± 27 vs. 24 ± 2 mg/day, respectively) and remained elevated until the end of the study. The kidneys from the SS LepR mutant strain displayed significant glomerular injury, including podocyte foot process effacement and lipid droplets compared with SS WT rats as early as 6 wk of age. By 18 wk of age, plasma creatinine levels were twofold higher in the SS LepR mutant strain vs. SS WT rats, suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SS LepR mutant strain develops podocyte injury and proteinuria independently of hyperglycemia and elevated arterial pressure that later progresses to CKD.