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Abstract: TH-PO778

A High-Power View of Renal Pathology of Sickle Cell Disease In Vivo

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Der, Balint, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Peti-Peterdi, Janos, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States
Background

Sickle cell disease (SCD) is commonly associated with chronic kidney disease. In SCD a mutation of the β-globin chain of hemoglobin (Hbb) causes the sickling of red blood cells (RBC). The complexity of renal histopathology in SCD is well recognized, however its pathogenesis is not fully understood. The purpose of this study was to improve the mechanistic understanding of the renal pathology development of SCD by establishing an intravital imaging model of the SCD kidney for the comprehensive, high-power quantitative visualization of renal morphology and function at the single cell and nephron level.

Methods

C57BL/6;129 female mice (5-8 weeks old) homozygous for both Hbbtm2(HBG1,HBB)Tow and Hbatm1(HBA)Tow mutations were used as a model of SCD. High resolution intravital multiphoton microscopy (MPM) of the intact living kidney was performed either in single-session or serial imaging.

Results

Compared to healthy control C57BL/6 mice, SCD mice displayed numerous enlarged superficial glomeruli with robust hyperdynamic vascular pathology and inflammation. Metabolites of hemoglobin degradation typical of the SCD environment (likely bilirubin) were readily detectable as green autofluorescence in the circulating plasma, and accumulated intracellularly in the glomerular mesangium and in tubular segments. Among the normally ‘doughnut’ shaped RBCs, sickled variants were also visible. Glomerular hyperfiltration was manifested by robustly increased glomerular diameter, and expanded Bowman’s space and tubular lumen. However, RBC velocity was decreased in glomerular capillaries, likely due to sickling and the observed numerous microthrombi, and the glomerulus-specific homing of different immune cell populations (CD3+ and CD44+). Albumin-Alexa594 uptake was visible in endothelial cells, podocytes, and proximal tubule cells. Over time, glomerular filtration barrier permeability increased progressively as evidenced by the robust filtration of albumin and 500 kDa dextran to the Bowman’s space by 8 weeks of age.

Conclusion

This study successfully performed in vivo MPM imaging of the SCD kidney, and directly visualized the impaired glomerular hemodynamics, endothelial and tubular injury, and chronic inflammation characteristic to SCD. MPM imaging of novel cellular and molecular mechanisms will help to improve our understanding of SCD kidney disease and to identify new targets for future therapeutic development.

Funding

  • NIDDK Support