Renal injury and progressive nephropathy is a major consequence of sickle cell disease (SCD) and is a cause of early mortality in this patient population. However, little is known about the molecular drivers that promote sickle cell nephropathy (SCN). Endothelin (ET) is a vasoconstrictor and pro-inflammatory peptide that is up-regulated in SCN. This presentation will provide preclinical data showing that specific blockade of the ET/ETA receptor pathway reduces the incidence of SCN. We will also provide data showing that endothelial-derived ET may specifically mediate SCN-induced immune cell activation, especially the Th17 pathway. Thus, we propose that the ET/ETA receptor pathway interacts with the activation of the Th17 pathway to promote SCN.