Modulation of Notch1 Signaling Alleviated Diabetic Nephropathy

  • Lin, Chun-Liang (PI)
  • Chang, Pey-Jium (CoPI)
  • Tseng, Min Jen (CoPI)
  • Wang, Feng Sheng (CoPI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

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
StatusFinished
Effective start/end date01/08/1131/07/12

Keywords

  • Notch1
  • diabetic nephropathy
  • VEGF
  • nephrin
  • podocyte

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.