Modulation of Notch-1 signaling alleviates VEGF mediated diabetic nephropathy
| Autor: | Yen-Chen Hsu, 許晏甄 |
|---|---|
| Rok vydání: | 2010 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 98 Diabetic nephropathy is a leading cause of end-stage renal disease in Taiwan. Vascular endothelial growth factor (VEGF), a survival and angiogenic factor with strong microvascular permeabilizing properties, may increase the permeability of the glomerular filtration barrier to circulating proteins. Studies using anti-VEFG antibody or VEGF receptor antagonists have suggested the systemic inhibition of VEGF that is capable of attenuating proteinuria. Furthermore, it is also noticed that increased VEGF activity in podocyte mediate the pathogenesis of FSGS and correlated with proteinuria in diabetic nephropathy. Thus, the regulation of VEGF must be subject to exquisite control in response to high glucose stresses to glomerular diseases. Recently, Notch receptors have to be reported play a critical role in cell fate decisions during developmental processes and maintaining tissue homeostasis. However, the biological mechanisms of Notch signaling pathway in regulation of diabetic proteinuria remains unclear. The biological role and control of the remodeling effect of Notch-1 signaling in order to alleviate diabetesinduced renal injury has not been tested. Notch-1 signaling modulators including γ -secretase inhibitor and superoxide scavenger alleviated the effect of high glucose on VEGF and nephrin expression in human podocytes. Interestingly, to delineate the role of the Notch signal pathway on the regulation of the VEGF expression, HEK293 cell lines expressing the N1IC were established and induced high glucose-stressed VEGF activation. We examined whether inhibition of Notch signaling by γ -secretase inhibitor could alter diabetes induced glomerulopathy in diabetic rats. In comparison with the normal group, γ-secretase inhibitor treatment significantly reduced the promoting effect of diabetes on urinary protein secretion. That Notch-1 is an emerging renal-deleterious factor that accelerates renal podocyte VEGF activation in high glucose-stressed renal tissue microenvironments. Modulation of Notch-1 signaling may be an innovative strategy for preventing diabetic nephropathy. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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