Moleculaire Mechanismen bij Sikkelcelnefropathie: Meer dan Alleen Apolipoproteïne L1-Gemedieerde Schade aan Podocyten

Sickle cell nephropathy (SCN) is the term for all kidney problems associated with sickle cell disease (SCD), including glomerular dysfunction. Proteinuria is the most sensitive early marker of glomerular dysfunction, progressing to end-stage kidney disease in about 20% of patients with SCD. The pathophysiology of kidney dysfunction in SCD remains unclear with recent studies pointing to the role of podocyte damage. However, the key players that may injure the podocytes still remain unexplored. In my previous work, I demonstrated that Apolipoprotein L1 (APOL1) high risk genotype (HRG) is associated with hyperfiltration and proteinuria in a pediatric population with SCD. I also observed that podocytes carrying APOL1 HRG have reduced cell viability upon exposure to hemoglobin for 24 hours. These data suggested that APOL1 HRG and cell-free hemoglobin might be key players in podocyte damage in SCN. Therefore, thegoal of this research project is to further unravel the mechanism of podocyte damage in SCN. For this purpose, I have formulated three objectives: (i) to establish a podocyte cell model from patients with SCD; (ii) to assess the role of oxidative stress as a consequence of hemolysis in the development of SCN; and (iii) to assess the role of APOL1 HRG in the development of SCN. The results obtained from this project will improve our knowledge in pathophysiology of SCN and in the development of therapies to reduce morbidity and mortality associated with SCD.