n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Proteinuria

Growth hormone (GH) plays a significant role in normal renal function and overactive GH signaling has been implicated in proteinuria in diabetes and acromegaly. Previous results have shown that the glomerular podocytes, which play an essential role in renal filtration, express the GH receptor, suggesting the direct action of GH on these cells. However, the exact mechanism and the downstream pathways by which excess GH leads to diabetic nephropathy is not established. In the present article, using immortalized human podocytes

Topics: Animals; Cells, Cultured; Cytokines; Diabetic Nephropathies; Dipeptides; Epithelial-Mesenchymal Transition; Growth Hormone; Humans; Male; Mice; Podocytes; Proteinuria; Receptor, Notch1; 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.

Topics: Animals; Case-Control Studies; Cell Cycle; Cell Death; Cell Differentiation; Cell Lineage; Cell Proliferation; Cells, Cultured; Dipeptides; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Female; Glomerulosclerosis, Focal Segmental; Humans; Lupus Nephritis; Mice; Mice, SCID; Podocytes; Proteinuria; Receptors, Notch; Severity of Illness Index; Stem Cells; Time Factors; Transfection