Title: The complex role of Notch3 in the kidney: Modulator of renal hemodynamics during development and initiator of CKD in adulthood
Jean-Claude Dussaule (MD- PhD) is currently Professor of Physiology, University UPMC (Paris VI) and Chief of Division of Physiology, at St-Antoine Hospital, Director of the Medical Pole “Spécialités Médicales” of “Hôpitaux de l’Est Parisien” (Paris, France). He is a member of the Research Unit: UMR702 Inserm-UPMC, and has published more than 110 papers referenced in PubMed. His expertise regarding experimental research is in the fields of renal and vascular endocrinology, renal fibrosis and hemodynamics and hypertension.
The Notch3 receptor is normally expressed in vascular smooth muscle cells and participates in the development and maturation of vessels. Mutations of Notch3 in humans are associated with defective regulation of cerebral blood flow. The role of Notch3 in the regulation of renal hemodynamics was investigated using mice lacking expression of the Notch3 gene (Notch3-/-). The renal vascular resistance of Notch3-/- varied little after exogenous administration of vasoconstrictor or vasodilator agents. Renal resistance microvessels of Notch3-/- showed a deficient contractile response to vasoconstrictors due to a lower entry of extracellular calcium. This abnormal response was attributed to a developmental deficiency of the maturation of VSMC leading to structural heterogeneity in the thickness of the renal vascular wall and the dysfunction of calcium entry channels. In separate studies we found that a de novo activation of expression of Notch3 occurred in the renal epithelium following aggression (UUO and anti-GBM models of nephropathy). This de novo activation initiated phenotype changes making epithelial cells to acquire a pro-inflammatory, pro-migratory phenotype. Notch3-/- or wild type mice treated with antisense oligodeoxynucleotides targeting Notch3 were protected as they exhibited less proteinuria, uremia and inflammatory infiltration. These results show an important and complex role for Notch3 in renal physiopathology. Activation of Notch3 during development contributes to the maturity of resistance vessels and is necessary for the adaptive response of the renal vasculature to vasoactive systems. In contrast, neo-activation of Notch3 in adulthood is detrimental as initiates and contributes to cellular events associated to loss of renal function.