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^LepRmutant strain). At 6 wk of age, body weight was 35% higher in the SS^LepRmutant strain compared with SS_WT rats and remained elevated throughout the entire study. The SS^LepRmutant 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^LepRmutant 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^LepRmutant 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^LepRmutant 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^LepRmutant strain vs. SS_WT rats, suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SS^LepRmutant strain develops podocyte injury and proteinuria independently of hyperglycemia and elevated arterial pressure that later progresses to CKD.

Keywords: CKD; Dahl S rats; leptin receptor; lipid droplets; obesity; podocyte injury.