Page 55 - Haematologica-5

Red Cell Biology & its Disorders
RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice
Alfia Khaibullina,1 Elena A. Adjei,1,2 Nowah Afangbedji,1 Andrey Ivanov,1 Namita Kumari,1 Luis E.F. Almeida,3 Zenaide M.N. Quezado,3 Sergei Nekhai1,4,5 and Marina Jerebtsova5
1Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC; 2Departments of Genetics and Human Genetics, College of Medicine, Howard University, Washington, DC; 3Department of Perioperative Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, MD; 4Department of Medicine, College of Medicine, Howard University, Washington, DC and 5Department of Microbiology, College of Medicine, Howard University, Washington, DC, USA
ABSTRACT
Sickle cell disease patients are at increased risk of developing a chron- ic kidney disease. Endothelial dysfunction and inflammation asso- ciated with hemolysis lead to vasculopathy and contribute to the development of renal disease. Here we used a Townes sickle cell disease mouse model to examine renal endothelial injury. Renal disease in Townes mice was associated with glomerular hypertrophy, capillary dilation and congestion, and significant endothelial injury. We also detected substantial renal macrophage infiltration, and accumulation of macrophage stimulating protein 1 in glomerular capillary. Treatment of human cultured macrophages with hemin or red blood cell lysates sig- nificantly increased expression of macrophage membrane-associated protease that might cleave and activate circulating macrophage stimulat- ing protein 1 precursor. Macrophage stimulating protein 1 binds to and activates RON kinase, a cell surface receptor tyrosine kinase. In cultured human renal glomerular endothelial cells, macrophage stimulating pro- tein 1 induced RON downstream signaling, resulting in increased phos- phorylation of ERK and AKT kinases, expression of Von Willebrand fac- tor, increased cell motility, and re-organization of F-actin. Specificity of macrophage stimulating protein 1 function was confirmed by treatment with RON kinase inhibitor BMS-777607 that significantly reduced downstream signaling. Moreover, treatment of sickle cell mice with BMS-777607 significantly reduced glomerular hypertrophy, capillary dilation and congestion, and endothelial injury. Taken together, our find- ings demonstrated that RON kinase is involved in the induction of renal endothelial injury in sickle cell mice. Inhibition of RON kinase activation may provide a novel approach for prevention of the development of renal disease in sickle cell disease.
Introduction
Sickle cell disease (SCD) is the most commonly inherited hematologic disorder caused by a single nucleotide mutation in the β-globin gene (HBB) resulting in HbS hemoglobin. HbS polymerization leads to sickling and hemolysis of red blood cells (RBCs), vaso-occlusion and organ damage. SCD patients are at increased risk of developing chronic kidney disease (CKD).1,2 Renal involvement in SCD can be pres- ent in childhood, as evidenced in 16-28% of children with clinical manifestations of proteinuria and microalbuminuria.3 Albuminuria and proteinuria are observed in more than 50% of adult SCD patients, and renal failure is developed in about 30%.4,5 SCD-associated nephropathy is characterized by tubular dysfunction, which is manifested by inability to concentrate urine, and consequent hypos- thenuria and polyuria, and glomerular damage. Glomerular abnormalities are char- acterized by glomerular hypertrophy, expansion of mesangium, thrombotic
Ferrata Storti Foundation
Haematologica 2018 Volume 103(5):787-798
Correspondence:
marina.jerebtsova@howard.edu
Received: September 15, 2017. Accepted: March 1, 2018. Pre-published: March 8, 2018.
doi:10.3324/haematol.2017.180992
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/787
©2018 Ferrata Storti Foundation
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Haematologica | 2018; 103(5)
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