Novel Endothelial and Immunologic Mechanisms of Pathophysiology in Sickle Cell Disease

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Project Summary Sickle cell disease was first identified in the US in 1910 and the first treatment was not proposed until the 1980’s. It is the first identified single gene causative disease and is the most common inherited blood disorder in the US. It presents when individuals inherit two mutant beta globin genes, one from each parent. Kidney disease is found in a large number of patients with sickle cell disease (sickle cell nephropathy) and can progress to death rapidly. Elevated levels of the peptide endothelin 1 and dysregulated immune function have been shown to play a major role in the development of sickle cell nephropathy, However, the cell source for the peptide and immune cell type by which this occurs is poorly misunderstood. The central hypothesis of the proposed studies is that, within the kidney, sickle cell disease promotes endothelial-specific endothelin 1 expression and TH17-mediated damage, leading to renal injury, dysfunction and overall nephropathy. To study the contribution of endothelial-derived endothelin 1, we successfully developed an endothelial-specific endothelin 1 knockout mouse model on the Townes humanized sickle cell mouse background. These animals will be studied rigorously in order to evaluate markers of renal injury and dysfunction, and will undergo studies to determine pathophysiological hallmarks of disease progression. To determine the innovative role of TH17 cells in sickle cell nephropathy, humanized mice will undergo flow cytometric and histopathologic analysis to determine temporal relationship between disease progression and immune cell infiltration. Furthermore, using established adoptive transfer experiments, SCD mice will have in vitro polarized TH17 cells from TH17 reporter mice transferred into them at a young age to evaluate the contribution long-term to sickle cell nephropathy. Finally, we will also evaluate whether endothelial- derived endothelin 1 has a role in the recent observation that SCD mice have elevated intrarenal TH17 cells. These two innovative approaches will seek to provide novel pathways by which to better target sickle cell nephropathy and ultimately improve outcomes for patients with sickle cell disease.