Abstract: TH-PO703
Long-Term P-Selectin Deficiency Does Not Prevent Progressive Renal Disease in Humanized Sickle Cell Mice
Session Information
- Anemia and Iron Metabolism
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Anemia and Iron Metabolism
- 200 Anemia and Iron Metabolism
Authors
- Kasztan, Malgorzata, The University of Alabama at Birmingham Department of Pediatrics, Birmingham, Alabama, United States
- Sparkenbaugh, Erica, The University of North Carolina at Chapel Hill Department of Medicine, Chapel Hill, North Carolina, United States
- Binning, Elizabeth, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Trebak, Fatima, The University of North Carolina at Chapel Hill Department of Medicine, Chapel Hill, North Carolina, United States
- Pawlinski, Rafal, The University of North Carolina at Chapel Hill Department of Medicine, Chapel Hill, North Carolina, United States
Background
Sickle cell disease (SCD) is a hemoglobinopathy characterized by chronic hemolysis, endothelial activation, and vaso-occlusion, ultimately leading to multiple organ damage. P-selectin is an adhesion molecule that mediates vascular stasis in SCD, and monoclonal antibody against P-selectin reduces the frequency of acute vaso-occlusive crisis in SCD patients. Sickle cell nephropathy is largely determined by renal vasculopathy, thus, we aimed to assess the effect of chronic P-selectin deficiency on kidney disease in murine model of SCD.
Methods
We evaluated kidney structure and function in 11-12 months old, male and female, humanized sickle cell (HbSS, n=14-17) and non-sickle control (HbAA, n=16-27) mice with or without P-selectin expression.
Results
The absence of P-selectin did not prevent progressive renal disease in HbSS mice as evidenced by hyposthenuria, proteinuria and loss of kidney function, determined by reduced GFR. We also determined if chronic P-selectin deficiency contributes to the development of glomerulopathy by measuring structural and functional markers of glomerular injury. Even though we observed a significant reduction in glomerular congestion score (0.16±0.05 vs. 0.37±0.06, p<0.05), P-selectin deficiency did not prevent albuminuria, glomerular sclerosis, hypertrophy, and podocyte loss in HbSS mice. Interestingly, significant hypercellularity, extensive mesangial expansion (2.3±0.1 vs. 1.3±0.1, p<0.05) and mesangiolysis were observed in P-selectin-/- HbSS when compared to P-selectin+/+ HbSS mice. We also examined the effect of P-selectin deficiency on tubular injury. Regardless of P-selectin genotype, HbSS mice had greater urinary KIM-1 excretion and tubular simplification with brush border loss than non-sickle control mice. Also, despite a reduction in inflammatory cell recruitment in the kidney, P-selectin-/- HbSS mice presented with the same degree of renal fibrosis as P-selectin+/+HbSS mice. Secondary to reduced macrophage renal recruitment P-selectin deficient HbSS mice had significantly elevated renal iron accumulation when compared to HbSS mice with normal P-selectin expression (12.2±1.1 vs. 8.8±0.6, p<0.05).
Conclusion
These results suggest that despite reducing vaso-occlusion chronic P-selectin deficiency does not prevent progressive kidney disease in murine model of SCD.
Funding
- Other NIH Support