%0 Journal Article %1 Bielesz.2010 %A Bielesz, B. %A Sirin, Y. %A Si, H. %A Niranjan, T. %A Gruenwald, A. %A Ahn, S. %A Kato, H. %A Pullman, J. %A Gessler, M. %A Haase, V. H. %A Susztak, K. %D 2010 %J J Clin Invest %K Amyloid Animals Basic Calcium-Binding Cell Cells/cytology/*metabolism Epithelial Factors/genetics/metabolism Failure;Chronic/metabolism/pathology Fibrosis/pathology Helix-Loop-Helix Homeodomain Humans Intercellular Kidney Kidney/cytology/*metabolism/*pathology Male Membrane Mice Mice;Transgenic Nephritis;Interstitial/metabolism/pathology Peptides;Proteins/genetics/metabolism Precursor Proliferation Protein Proteins/genetics/metabolism Receptor;Notch1/genetics/*metabolism Secretases/antagonists Signal Signaling Transcription Transduction/*physiology Tubules/*cytology inhibitors {\&} %N 11 %P 4040--4054 %R 10.1172/JCI43025. %T Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans %V 120 %X Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a gamma-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.

@article{Bielesz.2010, abstract = {Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a gamma-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.}, added-at = {2013-01-29T13:47:26.000+0100}, author = {Bielesz, B. and Sirin, Y. and Si, H. and Niranjan, T. and Gruenwald, A. and Ahn, S. and Kato, H. and Pullman, J. and Gessler, M. and Haase, V. H. and Susztak, K.}, biburl = {https://www.bibsonomy.org/bibtex/23b967e0be5d1534bb9ba5fc197cdbf1c/ebch}, doi = {10.1172/JCI43025.}, interhash = {d50aedca18802a6c11b1bee336086bdc}, intrahash = {3b967e0be5d1534bb9ba5fc197cdbf1c}, journal = {J Clin Invest}, keywords = {Amyloid Animals Basic Calcium-Binding Cell Cells/cytology/*metabolism Epithelial Factors/genetics/metabolism Failure;Chronic/metabolism/pathology Fibrosis/pathology Helix-Loop-Helix Homeodomain Humans Intercellular Kidney Kidney/cytology/*metabolism/*pathology Male Membrane Mice Mice;Transgenic Nephritis;Interstitial/metabolism/pathology Peptides;Proteins/genetics/metabolism Precursor Proliferation Protein Proteins/genetics/metabolism Receptor;Notch1/genetics/*metabolism Secretases/antagonists Signal Signaling Transcription Transduction/*physiology Tubules/*cytology inhibitors {\&}}, number = 11, pages = {4040--4054}, timestamp = {2013-01-29T13:47:39.000+0100}, title = {Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans}, volume = 120, year = 2010 }