Ectopic Notch Activation in Developing Podocytes Impairs Slit Diaphragm Formation and Induces Abnormal Podocyte Differentiation

Podocytes are terminally differentiated epithelial cells which regulate glomerular permselectivity by their cell-cell junctions, known as slit diaphragms (SD). Notch signaling regulates podocyte cell fate specification and downregulation of Notch targets occurs with terminal podocyte differentiation. The effects of constitutive Notch activation in developing podocytes on podocyte differentiation and function were determined using a podocyte-specific Cre-lox-p(Neph/Cre) approach. Proteinuria was noted shortly after birth denoting loss of glomerular permselectivity in transgenic mice (CRE;NIC mice). Histologic and molecular analyses of CRE;NIC-expressing mice at onset of proteinuria, show morphologic and cellular changes in podocytes including de-differentiation, proliferation and de novo expression of Pax2. Prior to onset of proteinuria, lower protein levels of key SD proteins are observed while SD mRNA expression is preserved in CRE;NIC mice. Consequently, constitutive Notch signaling in developing podocytes opposes terminal differentiation with deleterious consequences on SD assembly and thereafter, glomerular permselectivity.MAS