The Notch γ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation
Abstract
Kidney fibrosis is a common feature of chronic kidney disease (CKD). A recent study suggests that abnormal Notch signaling activation contributes to the development of renal fibrosis. However, the molecular mechanism that regulates this process remains unexplored. Unilateral ureteral obstruction (UUO) or sham-operated C57BL6 mice (aged 10 weeks) were randomly assigned to receive dibenzazepine (DBZ, 250 μg/100g/d) or vehicle for 7 days. Histologic examinations were performed on the kidneys using Masson's trichrome staining and immunohistochemistry. Real-time PCR and western blot analysis were used for detection of mRNA expression and protein phosphorylation. The expression of Notch 1, 3, and 4, Notch intracellular domain (NICD), and its target genes Hes1 and HeyL were upregulated in UUO mice, while the increase in NICD protein was significantly attenuated by DBZ. After 7 days, the severity of renal fibrosis and expression of fibrotic markers, including collagen 1α1/3α1, fibronectin, and α-smooth muscle actin, were markedly increased in UUO compared with sham mice. In contrast, administration of DBZ markedly attenuated these effects. Furthermore, DBZ significantly inhibited UUO-induced expression of transforming growth factor (TGF)-β, phosphorylated Smad 2, and Smad 3. Mechanistically, Notch signaling activation in tubular epithelial cells enhanced fibroblast proliferation and activation in a coculture experiment. Our study provides evidence that Notch signaling is implicated in renal fibrogenesis. The Notch inhibitor DBZ can ameliorate this process via inhibition of the TGF-β/Smad2/3 signaling pathway, and might be a novel drug for preventing chronic kidney disease.
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TGF-β is a Notch inhibitor upregulated during ageing and may explain the spontaneous entry of satellite cells into the cell cycle during ageing.
“Furthermore, TGF‐β is a Notch inhibitor upregulated during ageing and may explain the spontaneous entry of satellite cells into the cell cycle during ageing.[ 45 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [45]
Cites
Cellular and molecular mechanisms of renal fibrosis
Liu, Y. (2011) · Nature Reviews Nephrology · doi:10.1038/nrneph.2011.149 · Cited by 1,456 · see citing works
Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury
Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V., & Bonventre, J. V. (2010) · Nature Medicine · doi:10.1038/nm.2144 · Cited by 1,333 · see citing works
Origin and function of myofibroblasts in kidney fibrosis
LeBleu, V. S., Taduri, G., O’Connell, J. T., Teng, Y., Cooke, V. G., Woda, C. B., Sugimoto, H., & Kalluri, R. (2013) · Nature Medicine · doi:10.1038/nm.3218 · Cited by 1,267 · see citing works
Notch signaling: control of cell communication and cell fate
Lai, E. C. (2004) · Development · doi:10.1242/dev.01074 · Cited by 1,063 · see citing works
Tubulointerstitial Changes as a Major Determinant in the Progression of Renal Damage
Nath, K. A. (1992) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(12)80312-x · Cited by 977 · see citing works
Integration of TGF‐β/Smad and Jagged1/Notch signalling in epithelial‐to‐mesenchymal transition
Zavadil, J., C̆ermák, L., Soto-Nieves, N., & Böttinger, E. P. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600069 · Cited by 742 · see citing works
Milano, J., McKay, J., Dagenais, C., Foster-Brown, L., Pognan, F., Gadient, R. A., Jacobs, R. T., Zacco, A., Greenberg, B., & Ciaccio, P. J. (2004) · Toxicological Sciences · doi:10.1093/toxsci/kfh254 · Cited by 575 · see citing works
Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy?
Kriz, W., Kaissling, B., & Hir, M. L. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44595 · Cited by 456 · see citing works
Blokzijl, A., Dahlqvist, C., Reissmann, E., Falk, A., Moliner, A., Lendahl, U., & Ibáñez, C. F. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200305112 · Cited by 396 · see citing works
Bielesz, B. O., Sirin, Y., Si, H., Niranjan, T., Gruenwald, A., Ahn, S.-H., Kato, H., Pullman, J. M., Gessler, M., Haase, V. H., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci43025 · Cited by 345 · see citing works
Ma, F., Li, Y., Jia, L., Han, Y., Cheng, J., Li, H., Qi, Y., & Du, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035144 · Cited by 273 · see citing works
Self-citationWu, C.-F., Chiang, W., Lai, C., Chang, F., Chen, Y., Chou, Y., Wu, T.-H., Linn, G. R., Ling, H., Wu, K., et al. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.09.009 · Cited by 247 · see citing works
TGF-β/Smad Signaling in Kidney Disease
Lan, H. Y., & Chung, A. C. K. (2012) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2012.04.002 · Cited by 232 · see citing works
Murea, M., Park, J.-K., Sharma, S., Kato, H., Gruenwald, A., Niranjan, T., Si, H., Thomas, D. B., Pullman, J. M., Melamed, M. L., et al. (2010) · Kidney International · doi:10.1038/ki.2010.172 · Cited by 186 · see citing works
Okada, H., Kikuta, T., Kobayashi, T., et al. (2004) · Journal of the American Society of Nephrology · doi:10.1681/asn.2004040339 · Cited by 181 · see citing works
TGF-beta 1 induced fibroblast proliferation is mediated by the FGF-2/ERK pathway.
Xiao, L.-J., Du, Y., Shen, Y., He, Y., Zhao, H., & Li, Z.-H. (2012) · Frontiers in Bioscience · doi:10.2741/4077 · Cited by 148 · see citing works
Inhibition of Notch Signaling by a γ-Secretase Inhibitor Attenuates Hepatic Fibrosis in Rats
Chen, Y., Zheng, S., Qi, D., Zheng, S., Guo, J., Zhang, S., & Weng, Z. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046512 · Cited by 140 · see citing works
Yang, M. H., Zheng, J., Miao, Y., Wang, Y., Cui, W., Guo, J., Qiu, S., Han, Y., Jia, L., Li, H., et al. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.248732 · Cited by 139 · see citing works
Self-citationDees, C., Zerr, P., Tomčík, M., Beyer, C., Horn, A., Akhmetshina, A., Palumbo, K., Reich, N., Zwerina, J., Sticherling, M., et al. (2011) · Arthritis & Rheumatism · doi:10.1002/art.30254 · Cited by 129 · see citing works
Sassoli, C., Chellini, F., Pini, A., Tani, A., Nistri, S., Nosi, D., Zecchi‐Orlandini, S., Bani, D., & Formigli, L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063896 · Cited by 129 · see citing works
Aoyagi, K., Maeno, T., Matsui, H., Ueno, M., Hara, K., Aoki, Y., Aoki, F., Shimizu, T., Doi, H., Kawai‐Kowase, K., et al. (2011) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2010-0140oc · Cited by 118 · see citing works
Rastaldi, M. P. (2006) · Journal of Nephrology · doi:10.1093/joneph/19.4.407 · Cited by 117 · see citing works
Cheng, J., & Du, J. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.147371 · Cited by 114 · see citing works
Self-citationDjudjaj, S., Chatziantoniou, C., Raffetseder, U., Guerrot, D., Dussaule, J., Boor, P., Kerroch, M., Hanssen, L., Brandt, S., Dittrich, A., et al. (2012) · The Journal of Pathology · doi:10.1002/path.4076 · Cited by 102 · see citing works
Pan, L., Li, Y., Jia, L., Qin, Y., Qi, G., Cheng, J., Qi, Y., Li, H., & Du, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035315 · Cited by 92 · see citing works
Self-citationLi, Y., Zhang, C., Wu, Y.-N., Han, Y.-L., Cui, W., Jia, L., Cai, L., Cheng, J.-Z., Li, H.-H., & Du, J. (2012) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.249706 · Cited by 92 · see citing works
Self-citationMatsuno, Y., Coelho, A. L., Járai, G., Westwick, J. K., & Hogaboam, C. M. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.01.021 · Cited by 86 · see citing works
The story of Notch and chronic kidney disease
Sharma, S., Sirin, Y., & Suszták, K. (2010) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0b013e3283414c88 · Cited by 84 · see citing works
Hans, C. P., Koenig, S. N., Huang, N., Cheng, J., Beceiro, S., Guggilam, A., Kuivaniemi, H., Partida‐Sánchez, S., & Garg, V. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.254219 · Cited by 74 · see citing works
Cheng, J., Truong, L. D., Wu, X., Kuhl, D., Lang, F. J. W., & Du, J. (2010) · Kidney International · doi:10.1038/ki.2010.214 · Cited by 66 · see citing works
Self-citationNew Insights into the Mechanism of Notch Signalling in Fibrosis
Kavian, N., Servettaz, A., Weill, B. J., et al. (2012) · The Open Rheumatology Journal · doi:10.2174/1874312901206010096 · Cited by 57 · see citing works
Zhang, Y., Wang, Y., Liu, Y., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063424 · Cited by 51 · see citing works
Qiao, L., Xie, L., Shi, K., Zhou, T.-F., Hua, Y., & Liu, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051514 · Cited by 50 · see citing works
Zheng, Y.-H., Li, F., Tian, C., Ren, H., Du, J., & Li, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083310 · Cited by 44 · see citing works
Self-citationVachvanichsanong, P. (2007) · Journal of Nephrology · doi:10.1093/joneph/20.1.21 · Cited by 42 · see citing works
Human renal fibroblast contraction of collagen I lattices is an integrin‐mediated process
Kelynack, K. J., Hewitson, T. D., Nicholls, K., Darby, I. A., & Becker, G. J. (2000) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/15.11.1766 · Cited by 34 · see citing works
Notch1 mediates visfatin-induced FGF-2 up-regulation and endothelial angiogenesis
Bae, Y.-H., Park, H.-J., Kim, S.-R., Kim, J., Kang, Y., Kim, J., Wee, H., Kageyama, R., Jung, J. S., Bae, M., et al. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq276 · Cited by 32 · see citing works
Droy-Dupré, L., Vallée, M., Bossard, C. J., et al. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.007591 · Cited by 10 · see citing works
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Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review
Li, C., Yu, K., Shyh‐Chang, N., Jiang, Z., Liu, T., Ma, S., Luo, L., Guang, L., Liang, K., Ma, W., et al. (2022) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12901 · Cited by 626 · see citing works
- Authors
- Xiao, Z., Zhang, J., Peng, X., Dong, Y., Jia, L., Li, H., & Du, J.
- Affiliations
- Capital Medical University (CN)
- Corresponding author
- Du, Jie
- Venue
- The International Journal of Biochemistry & Cell Biology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 55
- Pages
- 65-71
- ISSN
- 1357-2725 (ISSN-L)
- OpenAlex
- W2093292834
- Cited by
- 80
- References
- 38
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 14 · 2016: 9 · 2015: 3
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The International Journal of Biochemistry & Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- renal fibrosis, Notch signaling, gamma-secretase inhibitors, dibenzazepine, TGF-β/Smad2/3 signaling, chronic kidney disease, unilateral ureteral obstruction, renal tubular epithelial cells, fibroblast activation, collagen deposition, Hes1, HEYL, Notch intracellular domain
- MeSH terms
- Animals, Cells, Cultured, Dibenzazepines, Fibrosis, Kidney, Kidney Diseases, Mice, Inbred C57BL, Random Allocation, Ureteral Obstruction, Blotting, Western, Signal Transduction, Gene Expression, Transforming Growth Factor beta, Reverse Transcriptase Polymerase Chain Reaction, Receptors, Notch, Smad2 Protein, Smad3 Protein, Amyloid Precursor Protein Secretases
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