title: Notch1 and Notch2 in Podocytes Play Differential Roles During Diabetic Nephropathy Development.
abstract: Notch pathway activation in podocytes has been shown to play an important role in diabetic kidney disease (DKD) development; however, the receptors and ligands involved in the process have not been identified. Here, we report that conditional deletion of Notch1 in podocytes using NPHS2(cre)Notch1(flox/flox) animals resulted in marked amelioration of DKD. On the contrary, podocyte-specific genetic deletion of Notch2 had no effect on albuminuria and mesangial expansion. Notch1-null podocytes were protected from apoptosis and dedifferentiation in vitro, likely explaining the protective phenotype in vivo. Deletion of Notch1 in podocytes also resulted in an increase in Notch2 expression, indicating an interaction between the receptors. At the same time, transgenic overexpression of Notch2 in podocytes did not induce phenotypic changes, while constitutive expression of Notch1 caused rapid development of albuminuria and glomerulosclerosis. In summary, our studies indicate that Notch1 plays a distinct (nonredundant) role in podocytes during DKD development.
authors: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Mariya T
authors: MT
authors: Sweetwyne
authors: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Antje
authors: A
authors: Gruenwald
authors: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Thiruvur
authors: T
authors: Niranjan
authors: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Ryuichi
authors: R
authors: Nishinakamura
authors: Department of Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.
authors: Lothar J
authors: LJ
authors: Strobl
authors: Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA ksusztak@mail.med.upenn.edu.
authors: Katalin
authors: K
authors: Susztak
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D054337:Cell Dedifferentiation; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D015415:Biomarkers; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D010446:Peptide Fragments; D012333:RNA, Messenger; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011994:Recombinant Proteins