Abstract P265: Early Renal Hyperfiltration In Obese Dahl Salt-Sensitive Leptin Receptor Mutant Rats is Associated With Glomerular Leukocyte Extravasation and Renal Disease

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2018-09, Vol.72 (Suppl_1)
• Main Authors: Williams, Jan M, McPherson, Kasi C, Shields, Corbin A, Poudel, Bibek, Cornelius, Denise C, Garrett, Michael R
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.72.suppl_1.P265

Abstract only Hypertension and diabetes are the major causes of chronic kidney disease (CKD). However, epidemiological studies within the last few decades have revealed obesity as an independent risk factor for CKD. Recently, we reported that the obese Dahl salt-sensitive leptin receptor mutant (SS LepR mutant) strain displays proteinuria and podocyte injury by 6 weeks of age independent of hyperglycemia and elevations in arterial pressure. The current study examined whether the development of renal injury in the SS LepR mutant strain is associated with elevations in glomerular filtration rate (GFR). During the study, the SS LepR mutant strain developed hyperinsulinemia and dyslipidemia but not hyperglycemia. Baseline MAP (via carotid catheter) at 6 weeks of age was similar between SS WT (n=8) and SS LepR mutant (n=8) rats and averaged 124 mmHg. However, by 18 weeks of age, MAP increased significantly in the SS LepR mutant strain compared to the values measured in SS WT rats (192±4 vs 149±6 mmHg, respectively). At baseline, protein excretion was 4-fold higher in the SS LepR mutant strain compared to SS WT rats and remained elevated over the course of the study (778±96 vs 137±25 mg/day, respectively). At 6 weeks of age, GFR was 34% higher in the SS LepR mutant strain compared to age-matched SS WT rats indicating renal hyperfiltration (2.92±0.23 vs 2.18±0.25 mL/min/kwt, respectively). While we observed only a 40% reduction in GFR in SS WT rats (1.30±0.07 mL/min/kwt), GFR markedly decreased by 70% in the SS LepR mutant strain (0.87±0.08 mL/min/kwt). Over time, kidneys from the SS LepR mutant strain displayed more glomerulosclerosis, mesangial expansion, and renal fibrosis in comparison to SS WT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 weeks of age and RNA sequencing was performed to identify genes and pathways driving glomerular injury. The major, most consistent signaling pathways that changed at 6 and 18 weeks of age were involved in leukocyte extravasation. In conclusion, these data provide evidence that renal hyperfiltration may contribute to glomerular capillary leukocyte extravasation leading to the early development of proteinuria during obesity in the absence of hypertension and hyperglycemia.