Sickle cell disease (SCD) is caused by a single nucleotide mutation in the ?-globin gene resulting in the polymerization of hemoglobin (HbS) in red blood cells (RBCs) under low oxygen conditions leading to hemolysis and vaso-occlusion. SCD is the most common hereditary disorder which affects approximately 100,000 people in the USA, primarily of African descent. Renal complications are the most common complications in SCD patients. They range from various tubular and glomerular functional abnormalities to gross anatomic alterations of the kidney. Overall, SCD patients have an approximately three-fold higher risk to develop chronic kidney disease (CKD) than the general population. More than 50% of SCD patients develop CKD in association with comorbidities and early mortality. However, the current standards of diagnosis and care can only delay progression of this disease. This is due to a lack of effective therapies and an absence of reliable assays for diagnosis of the early disease, before renal damage is severe or irreversible. New diagnostic and therapeutic tools are urgently needed. Development of these tools requires an improved understanding of the disease mechanism and identification of new biomarkers of disease onset and progression. The majority of renal complications of SCD result from functional vasculopathy and endothelial injury. In contrast, the key event in the development of glomerular complications leading to CKD is podocyte injury. This highlights a major gap in our knowledge of the mechanism of glomerular disease development in SCD. This proposal lays out a sophisticated approach to validate the role of hepatocyte growth factor like (HGFL) protein in the development of CKD in SCD. We hypothesize that RBC hemolysis products activate protease in infiltrated renal macrophages inducing a cascade of circulating HGFL activation and glomerular endothelial and epithelial cell injury.
In Aim 1, macrophage activation by the products of sickle RBC hemolysis and its role in the development of glomerular injury will be studied.
In Aim 2, the role of HGFL and its receptor, RON, in the induction of glomerular podocytes injury will be evaluated.
In Aim 3, target-specific quantitative assays, e.g. ELISA and single reaction monitoring mass-spectrometry will be used to validate correlation of urinary HGFL levels with estimated glomerular filtration rates (eGFR) in case-control study using Howard University Center for Sickle Cell Disease repository samples. This proposal is designed to evaluate the role of HGFL in the development of glomerular injury in SCD and validate HGFL as a novel diagnostic tool for hyperfiltration detection. A faculty research enhancement plan includes a strategy that will lead to developing an independently-funded basic and translational research program in SCD renal disease.
Sickle cell disease patients are at high risk of development of chronic kidney disease and early death. The proposed research is relevant to the public health because it is aimed at understanding of the mechanism of kidney disease and developing a novel clinical test for early disease detection. Uncovering a novel mechanism of kidney disease will lead to the development of novel therapeutic approaches specific for sickle cell disease.
