Project Details
Abstract
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. Interestingly,
Kopan et al have shown that inhibition of γ-secretase activity results in a severe deficiency in proximal
tubules and glomerular podocytes. Although previous studies have showed that abrogated the VEGF
secretion could ameliorate the proteinurina in diabetic animal model. 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 Notch1 signaling in order to alleviate diabetesinduced
renal injury has not been tested. We preliminarily found that Induction of Notch1, Hes-1, and
VEGF mRNA expression, but down-regulates nephrin expression were noted in high glucose stressed
human podocyte. Notch1 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 byγ -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 .
We hypothesize that Notch1 is an emerging renal-deleterious factor that accelerates renal podocyte
VEGF activation in high glucose-stressed renal tissue microenvironments. Modulation of Notch1
signaling may be an innovative strategy for preventing diabetic nephropathy. The rationale and
specific aims of the current project are outlined below:
Project IDs
Project ID:PC10001-0216
External Project ID:NSC98-2314-B182A-097-MY3
External Project ID:NSC98-2314-B182A-097-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/11 → 31/07/12 |
Keywords
- Notch1
- diabetic nephropathy
- VEGF
- nephrin
- podocyte
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