Addressing the pathophysiology of venous thrombosis and chronic kidney disease in sickle cell trait using a mouse model

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.