Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

Juillerat‐Jeanneret, Lucienne; Flohr, Alexander; Schneider, Manfred; Walter, Isabelle; Wyss, Jean-Christophe; Kumar, Randhir; Golshayan, Déla; Aebi, Johannes D.

doi:10.1021/acs.jmedchem.5b00912

Cited by 13 publications

(16 citation statements)

References 42 publications

(115 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another most important and bewildering problem is that we observed a significant increase in myeloid differentiation after knock-down of the Notch1 by shRNA, while no such effect was found in GSI mediated Notch 1 knock-down. As a member of hydrolytic enzyme families, DAPT can hydrolyze Notch binding protein to block the Notch signal, and is also considered to have the effect to down regulate the Notch1 expression at the mRNA level [ 24 ]. We speculate that there might be other influential factors in the differentiation of mDCs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Notch 1 receptor influenced the differentiation of Lin-CD45RA-dendritic cell precursors within ovarian carcinoma microenvironment

et al. 2016

View full text Add to dashboard Cite

BackgroundPrevious evidence suggested that the differentiation of Lin-CD45RA-DC precursors were prior to plasmcytoid dendritic cells (pDCs) than myeloid dendritic cells (mDCs) within ovarian cancer microenvironment. However, the mechanism is still unclear. Therefore, we investigated the function of Notch 1 signal pathway in the differentiation of Lin-CD45RA-DC precursors.MethodsThe CD34+ hematopoietic stem cells were extracted from umbilical cord blood in term parturition, and Lin-CD45RA-DC precusors were separated and induced mature. Expression of Notch1 receptor and ligands in Lin-CD45RA-DC precusors was detected by Real-time PCR and was down-regulated by shRNA or γ-secretase inhibitor (GSI). Flow cytometry was used to analyze the subset of DCs with or without SKOV3 culture supernatants. IL-12 level was detected by ELISA.ResultsExpression of Notch1 receptors and ligands were detected in Lin-CD45RA-DC precursor cells. The Notch1 mRNA in Lin-CD45RA-DC precursors can be down-regulated by shRNA-Notch1 lentivirus transfection and GSI. ShRNA mediated Notch 1 knock-down significantly differentiated less plasmcytoid dendritic cells (pDCs), but generated more myeloid dendritic cells (mDCs), and this would not be influenced by the supernatant of the ovarian carcinoma cell line. GSI had the same effect in the differentiation of pDC. The secretion of IL-12 significantly increased after Notch1 knock-down with or without SKOV3 culture supernatants.ConclusionsNotch1 is an important signaling pathway in the differentiation of Lin-CD45RA-DC precursor cells to plasmcytoid dendritic cells (pDCs). And this would not be affected by the supernatant of the ovarian carcinoma cell line.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of Notch 1 receptor influenced the differentiation of Lin-CD45RA-dendritic cell precursors within ovarian carcinoma microenvironment

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In a recent approach, 162 synthetic or non-GSI biological molecules, such as bioengineered antibodies or antagonists. 162,163 No large multicenter phase III clinical trial has yet been initiated, therefore it is premature to foresee the future of these therapeutics, but the tolerability profile has been shown to be acceptable (at least in the context of cancer) in early phase I/II clinical trials.…”

mentioning

confidence: 99%

Notch Antagonists: Potential Modulators of Cancer and Inflammatory Diseases

2016

Self Cite

View full text Add to dashboard Cite

Notch is a key player in various developmental processes during the embryonic stage as well as in regulating tissue homeostasis, cell differentiation, and stem cell maintenance in adult life. Activation of Notch signaling occurs following Notch receptor-ligand interaction and subsequent enzymatic proteolysis by the gamma-secretase complex, resulting in the cytoplasmic release of a Notch intracellular domain, which translocates to the nucleus to initiate the downstream transcriptional machinery. Notch activation and its aberrant signaling have been broadly linked to the pathogenesis of cancer and some chronic inflammatory diseases resulting in pathologic fibrotic processes. This review focuses on the molecular basis of Notch-induced signaling and its interaction with other pathways to identify therapeutic targets. We also highlight current efforts to pharmacologically intervene in Notch signaling and discuss promising ongoing experimental and clinical studies.

show abstract

“…The protein Notch-1 has a representative receptor in the Notch protein family, and its downstream intracellular domain is deemed a key target for therapy in various kidney diseases 22 . Studies have demonstrated that aberrant activation of the Notch-1 pathway has an important role in the processes associated with podocyte injury in DN 23 – 25 . The NICD translocates into the nucleus and associates with DNA-binding proteins to form a DNA-bound transcription factor that can also activate expression of target genes 22 , 26 .…”

Section: Discussionmentioning

confidence: 99%

Aberrant activation of Notch-1 signaling inhibits podocyte restoration after islet transplantation in a rat model of diabetic nephropathy

Zhang

et al. 2018

Cell Death Dis

View full text Add to dashboard Cite

Signaling abnormalities play important roles during podocyte injury and have been indicated as crucial events for triggering many glomerular diseases. There is emerging evidence demonstrating significant improvements in preventing renal injury and restoring podocytes after islet transplantation. However, whether signaling abnormalities affect the therapeutic efficacy of islet transplantation remain unclear. This study was established to investigate the impact of Notch-1 signaling activation on renal injury and podocyte restoration after islet transplantation. Experiments were performed in vivo and in vitro under conditions of diabetic nephropathy and high-glucose medium, respectively. Podocyte injury in vitro was induced by high-glucose concentration, and expression levels of genes associated with the Notch-1 pathway were also regulated by Jagged-1/FC and N-[N-(3,5-Difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT). Podocytes were co-cultured with islets to investigate the protective effect of islets in high-glucose conditions. Histopathological staining and transmission electron microscopy were performed to assess pathological changes in podocytes in glomeruli. The results from this study showed that Notch-1 signaling in podocytes was significantly decreased by functional islet cells in vivo and in vitro. Compared with the co-cultured group and transplanted group, highly activated Notch-1 signaling significantly moderated the effect of islets in affecting podocyte restoration and renal injury. Renal damage and podocyte injury were alleviated after DAPT treatment. Furthermore, the balance between apoptosis and autophagy was diverse under different treatments. All the data in this study showed that highly activated Notch-1 signaling could affect the therapeutic efficacy of islet transplantation on renal injury and podocyte restoration in high-glucose conditions. The balance between apoptosis and autophagy was also closely associated with the degree of podocyte restoration. This finding may suggest that the in vivo microenvironment plays a critical role in podocyte restoration after islet transplantation, which provides a promising and individual assessment and targeting treatment for different diabetic nephropathy patients after islet transplantation into the future.

show abstract

Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

Cited by 13 publications

References 42 publications

Inhibition of Notch 1 receptor influenced the differentiation of Lin-CD45RA-dendritic cell precursors within ovarian carcinoma microenvironment

Inhibition of Notch 1 receptor influenced the differentiation of Lin-CD45RA-dendritic cell precursors within ovarian carcinoma microenvironment

Notch Antagonists: Potential Modulators of Cancer and Inflammatory Diseases

Aberrant activation of Notch-1 signaling inhibits podocyte restoration after islet transplantation in a rat model of diabetic nephropathy

Contact Info

Product

Resources

About