Endothelial Dysfunction in the Pathogenesis of Sickle Cell Nephropathy

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Abstract Although it is recognized that sickle cell disease (SCD) is characterized by the presence of endothelial dysfunction, the contribution of endothelial dysfunction to disease pathophysiology remains poorly defined. We, and others, have previously reported on an association of pulmonary hypertension and nephropathy in patients with SCD, suggesting that they may share a similar pathophysiology. More recently, we have found that SCD patients with macroalbuminuria (urine albumin excretion > 300 mg/g creatinine) have significantly elevated levels of both soluble vascular cell adhesion molecule-1 (VCAM-1), a measure of endothelial activation, and soluble fms-like tyrosine kinase-1 (sFLT-1), a member of the VEGF receptor family. sFLT-1 is known to induce endothelial dysfunction by sequestration of VEGF in plasma and/or by the formation of inactive receptors and reduced signal transduction. In addition, we found that sFLT-1 was significantly correlated with soluble VCAM-1 in SCD patients. This data, combined with the association of sFLT-1 with proteinuria in other disease states (such as preeclampsia) suggests that by inducing endothelial dysfunction, sFLT-1 may play an important role in the development of albuminuria in SCD. In the current application, we will define the contribution of endothelial dysfunction as well as the sFLT-1/VEGF axis to the pathogenesis of albuminuria in SCD patients and transgenic sickle cell mice. Furthermore, we will evaluate the effect of atorvastatin, an agent that is known to attenuate endothelial dysfunction and decrease sFLT-1 release, on endothelial dysfunction and albuminuria. With the limited therapies available for the treatment of SCD-related nephropathy, the demonstration of a role for endothelial dysfunction in the pathogenesis of albuminuria will facilitate the development of more effective treatments.