DESCRIPTION (provided by applicant): Sickle Cell Disease is the most common inherited blood disorder in the United States and arises when affected individuals are homozygous for a mutant form of beta globin. Renal disease in patients with sickle cell disease (sickle cell nephropathy) occurs in a significant subset of patients and often rapidly progresses to renal failure. Decreased renal vascular nitric oxide production plays a major role in the development of sickle cell nephropathy. However, the mechanisms that contribute to this decreased nitric oxide production are poorly understood. The central hypothesis of the proposed studies is that, within renal vascular endothelial cells, sickle cell disease causes increased endothelin-1 (ET-1) production and increased histone deacetylase 1 (HDAC1) activity that lead to decreased nitric oxide production and, subsequently, renal injury and sickle cell nephropathy. In order to study the contribution of ET-1, we are developing an endothelial-specific ET-1 knockout mouse on a humanized sickle cell disease mouse background. These animals will be studied in order to determine markers of renal vascular nitric oxide production, and additionally, will undergo studies to evaluate renal function and renal injury. To determine the contribution of increased HDAC1 activity in renal vascular endothelial cells, humanized sickle cell disease mice will be treated with the HDAC1 inhibitor MS-275 and the clinically approved HDAC inhibitor, vorinostat. Following treatment, experiments used in the ET-1 aim will be utilized to investigate nitric oxide production, renal function, and renal damage.

PUBLIC HEALTH RELEVANCE: Sickle cell nephropathy is a significant complication of sickle cell disease and often rapidly progresses to renal failure. Decreased nitric oxide production by renal vascular endothelial cells is a major contributor to the development of sickle cell nephropathy, and the proposed study will investigate two novel mechanisms which lead to decreased nitric oxide production in by renal endothelial cells.