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Addressing the pathophysiology of venous thrombosis and chronic kidney disease in sickle cell trait using a mouse
Fatima Trebak1, Mohammad O Sako2, Steven P Grover1
1Division of Hematology and Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Insights
Sickle cell trait (SCT) in mice causes red blood cells to sickle in the kidneys and venous clots, leading to kidney dysfunction and larger thrombi. This mouse model mimics human SCT complications, aiding research into thrombosis and kidney disease.
Area of Science:
- Hematology
- Nephrology
- Thrombosis research
Background:
- Sickle cell trait (SCT) is linked to increased risk of venous thrombosis and kidney disease.
- Conditions like hypoxia, dehydration, and acidosis can trigger red blood cell (RBC) sickling in SCT.
Purpose of the Study:
- To investigate if Townes sickle trait (AS) mice develop kidney dysfunction and enhanced venous thrombosis.
- To evaluate the impact of the renal medulla environment on RBC sickling in AS mice.
Main Methods:
- Utilized Townes AS mice and control AA littermates.
- Assessed kidney function (urinary concentration, albuminuria, renal function).
- Employed an inferior vena cava model to study venous thrombosis under hypoxic conditions.
Main Results:
- The renal inner medulla induced in vitro and in vivo RBC sickling in AS mice.
- AS mice exhibited impaired urinary concentration, albuminuria, and declining renal function.
- Venous thrombi in AS mice showed irreversible RBC sickling and were larger than in controls.
Conclusions:
- Townes AS mice develop kidney pathologies mimicking human SCT.
- AS mice demonstrate enhanced venous thrombosis due to hypoxia-induced RBC sickling.
- These mice are a valuable model for studying SCT-related venous thrombosis and kidney disease.
Abstract:
Sickle cell trait (SCT) is present in participants who possess a single copy of the βS-globin gene mutation. Although most affected individuals are asymptomatic, SCT is a well-established risk factor for venous thrombosis and renal complications, including chronic and end-stage kidney disease. After prolonged hypoxia, SCT red blood cells (RBCs) can undergo sickling, and hypoxia-mediated RBC sickling can be enhanced by cellular dehydration, hyperosmolarity, and/or acidosis. Some or all of these conditions may be encountered in the nidus of venous thrombi and in the medulla of the kidney. We sought to determine whether Townes sickle trait (AS) mice develop kidney dysfunction and manifest enhanced venous thrombosis. We demonstrated that the harsh environment within the inner medulla induces RBC sickling in vitro and in vivo and is associated with kidney-related pathologies, including impaired urinary concentration, albuminuria, and declining renal function, closely mimicking those seen in human SCT. In the inferior vena cava model of venous thrombosis, extreme and prolonged hypoxia in the core of RBC-rich venous thrombi resulted in irreversible RBC sickling and larger clots in Townes AS mice than AA controls (littermates expressing hemoglobin A only). Our results support the use of Townes AS mice in future studies investigating mechanisms of venous thrombosis and chronic kidney disease in SCT.
