Preventive Effect of Notch Signaling Inhibition by a γ-Secretase Inhibitor on Peritoneal Dialysis Fluid-Induced Peritoneal Fibrosis in Rats

Abstract

Peritoneal fibrosis, a major complication of peritoneal dialysis, limits the effectiveness of peritoneal dialysis as a treatment of end-stage renal disease. Preventing this complication by identifying targets for therapy has recently received much attention. In the present study, we showed that Notch signaling was highly activated in rats in peritoneal dialysis fluid-induced fibrotic peritoneum, as indicated by increased expression of Jagged-1, Notch-1, and HES-1. Blocking Notch signaling activation by intraperitoneal injection of a gamma-secretase inhibitor, DAPT, significantly attenuated peritoneal fibrosis as indicated by the decreased expression of alpha-smooth muscle actin, collagen I, and vascular endothelial growth factor as well as increased expression of E-cadherin. Moreover, compared with control rats, DAPT-treated rats had a thinner peritoneum with less extracellular matrix accumulation, a lower mass transfer of glucose, and a higher ultrafiltration rate. In addition, transforming growth factor (TGF)-beta1 induced Notch signaling activation in primary rat peritoneal mesothelial cells. DAPT blocked this TGF-beta1-induced Notch signaling activation and therefore significantly inhibited TGF-beta1-induced expression of alpha-smooth muscle actin, collagen I, and vascular endothelial growth factor. Thus, a gamma-secretase inhibitor that interferes with Notch signaling prevents biochemical, histological, and functional consequences of peritoneal fibrosis through inhibiting epithelial to mesenchymal transition of rat peritoneal mesothelial cells. These results support the use of gamma-secretase inhibitors as a novel therapeutic approach for peritoneal fibrosis.

Functional and structural alterations of peritoneum and secretion of fibrotic cytokines in rats caused by high glucose peritoneal dialysis solutions

“…9,10 Experiments showed that inhibition of TGF-b1 bioactivity can attenuate extracellular matrix (ECM) deposition and the progression of tissue fibrosis in different experimental models. [11][12][13] Nevertheless, TGF-b1 plays a complicated and controversial role in an immune regulation due to its highly pleiotropic properties and the presence of TGF-b1 receptors on most cell types. As one of the key negative regulators of immune homeostasis, the absence of TGF-b1 leads to activation of a self-targeted immune response, raising concern about the long-term consequence of its suppression.…”

Blocking TGF-β1 Protects the Peritoneal Membrane from Dialysate-Induced Damage

“…36 -40 Furthermore, inhibition of TGF-␤1-induced Smad-independent pathways ameliorates the peritoneal membrane alterations in different experimental models. 41 However, the potential protective effects for the peritoneal membrane of agents directly targeting TGF-␤1 have not been explored.…”

Angiogenic Activity of the Peritoneal Mesothelium: Implications for Peritoneal Dialysis

“…Notch receptors are involved in the determination of cell fate, differentiation, and maintenance. The inhibition of Notch signalling resulted in the attenuation of both TGF-1-induced EMT in vitro and PD fluid-induced EMT and peritoneal fibrosis in vivo (Zhu et al, 2010). Importantly, in both processes, the blockade of Notch led to a decrease in mesothelial cell VEGF expression.…”

“…Moreover, PD fluid-induced EMT of mesothelial cells in rats could be substantially reduced by peritoneal rest (Yu et al, 2009), which has long been advocated as a means of restoring ultrafiltration in patients with the hyperpermeable peritoneum (de Alvaro et al, 1993;Rodrigues et al, 2002). It has also been demonstrated that PD fluid-induced EMT was associated with increased signalling from Notch receptors in www.intechopen.com mesothelial cells and the process was mediated through TGF-1 (Zhu et al, 2010). Notch receptors are involved in the determination of cell fate, differentiation, and maintenance.…”