Abstract 229: Genetic inhibition of Notch3 protects animals against Chronic Kidney Disease.
In the present study, we show that expression of the Notch3 receptor in glomeruli is associated to the development of renal disease and that inhibition of this expression is accompanied by renoprotection.
In a model of rapidly progressive glomerulonephritis (nephrotoxic serum-induced renal disease), Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. In contrast, mice with genetic ablation of Notch3 expression (KO) were protected as they showed less proteinuria, uremia and renal inflammation. In vitro studies suggested that podocytes expressing active Notch3 acquire a migratory and pro-inflammatory phenotype. To evaluate whether inhibiting Notch3 could be of therapeutic interest, we administered antisense oligodeoxynucleotides targeting Notch3 in wild type mice concomitantly to the disease induction, whereas scrambled sequences were used as controls. Both groups of mice developed renal disease, but mice injected with Notch3 antisense were protected compared to the scrambled group, as evidenced by the decreased values of plasma urea and proteinuria. In addition, the improvement of renal function was accompanied by fewer crescent formations and less deposits of fibrin within the glomeruli, and by decreased peritubular inflammation.
These results demonstrate that abnormal activation of Notch3 in the kidneys is involved in the progression of renal disease by promoting migratory and pro-inflammatory pathways and that blocking this activation preserves renal function and structure. Inhibiting Notch3 activation could be a novel, promising approach to treat chronic renal disease.
Author Disclosures: Z. Keuylian: None. F. El Machhour: None. J. Dussaule: None. C. Chatziantoniou: None.
- © 2014 by American Heart Association, Inc.