Notch Activation Differentially Regulates Renal Progenitors Proliferation and Differentiation Toward the Podocyte Lineage in Glomerular Disorders

• Published in: Stem cells (Dayton, Ohio) Vol. 28; no. 9; pp. 1674 - 1685
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2010
• Subjects: Animals; Case-Control Studies; Cell Cycle; Cell Death; Cell Differentiation - drug effects; Cell Lineage - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Dipeptides - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Female; Glomerulonephritis; Glomerulosclerosis; Glomerulosclerosis, Focal Segmental - chemically induced; Glomerulosclerosis, Focal Segmental - metabolism; Glomerulosclerosis, Focal Segmental - pathology; Humans; Kidney; Lupus Nephritis - metabolism; Lupus Nephritis - pathology; Mice; Mice, SCID; Podocytes - drug effects; Podocytes - metabolism; Podocytes - pathology; Proteinuria - metabolism; Proteinuria - pathology; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - genetics; Receptors, Notch - metabolism; Renal progenitors; Renal stem cells; Severity of Illness Index; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - pathology; Time Factors; Tissue-Specific Stem Cells; Transfection
• ISSN: 1066-5099; 1549-4918; 1549-4918
• DOI: 10.1002/stem.492

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 G2/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. STEM CELLS 2010; 28:1674–1685.