Initial characterization of leptin receptor knockout Dahl salt‐sensitive rats (1121.2)

Obesity‐induced metabolic syndrome (MetS) has grown at an alarming rate within the last decade and has been associated with the development of chronic kidney disease (CKD). In the current study, we created a 16 base pair frame‐shift deletion in exon 11 of the leptin receptor gene within the genetic background of the Dahl SS rat (SS Lepr ‐/‐ strain) using Zinc‐finger nucleases to study the effect of obesity on the progression of renal injury in SS rats. At 6 weeks of age, body weight was 45% higher in the SS Lepr ‐/‐ strain compared to SS WT rats and remained markedly elevated throughout the entire study (22 weeks of age). The SS Lepr ‐/‐ strain exhibited impaired glucose tolerance and increased plasma insulin levels as early as 6 weeks of age suggesting insulin resistance while SS WT rats did not. However, glucose levels remained in the normal range throughout the course of the study. At 22 weeks of age, the SS Lepr ‐/‐ strain developed severe systolic hypertension compared to the values observed in SS WT rats (242±17 vs. 158±6 mmHg, respectively). After 22 weeks of age, proteinuria increased to 618±36 mg/day in the SS Lepr ‐/‐ strain while it only increased to 136±28 mg/day in SS WT rats. The SS Lepr ‐/‐ strain exhibited more glomerular injury and renal fibrosis compared to SS WT rats. Overall, these data indicate that the SS Lepr ‐/‐ strain may be a useful model to study signaling pathways that play a role in CKD associated with MetS. Grant Funding Source : Supported by P20GM104357