
Notch Activation Differentially Regulates Renal Progenitors Proliferation and Differentiation Toward the Podocyte Lineage in Glomerular Disorders
Author(s) -
Lasagni Laura,
Ballerini Lara,
Angelotti Maria Lucia,
Parente Eliana,
Sagrinati Costanza,
Mazzinghi Benedetta,
Peired Anna,
Ronconi Elisa,
Becherucci Francesca,
Bani Daniele,
Gacci Mauro,
Carini Marco,
Lazzeri Elena,
Romagnani Paola
Publication year - 2010
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.492
Subject(s) - podocyte , biology , glomerulosclerosis , progenitor cell , notch signaling pathway , microbiology and biotechnology , progenitor , focal segmental glomerulosclerosis , kidney , glomerulonephritis , endocrinology , medicine , cancer research , stem cell , proteinuria , signal transduction
Glomerular diseases account for 90% of end‐stage kidney disease. Podocyte loss is a common determining factor for the progression toward glomerulosclerosis. Mature podocytes cannot proliferate, but recent evidence suggests that they can be replaced by renal progenitors localized within the Bowman's capsule. Here, we demonstrate that Notch activation in human renal progenitors stimulates entry into the S‐phase of the cell cycle and cell division, whereas its downregulation is required for differentiation toward the podocyte lineage. Indeed, a persistent activation of the Notch pathway induced podocytes to cross the G 2 /M checkpoint, resulting in cytoskeleton disruption and death by mitotic catastrophe. Notch expression was virtually absent in the glomeruli of healthy adult kidneys, while a strong upregulation was observed in renal progenitors and podocytes in patients affected by glomerular disorders. Accordingly, inhibition of the Notch pathway in mouse models of focal segmental glomerulosclerosis ameliorated proteinuria and reduced podocyte loss during the initial phases of glomerular injury, while inducing reduction of progenitor proliferation during the regenerative phases of glomerular injury with worsening of proteinuria and glomerulosclerosis. Taken altogether, these results suggest that the severity of glomerular disorders depends on the Notch‐regulated balance between podocyte death and regeneration provided by renal progenitors. S TEM C ELLS 2010; 28:1674–1685.