Ischemic acute kidney injury (AKI) is associated with high morbidity and frequent complications. Repeated episodes of AKI may lead to end-stage renal failure. The pathobiology of regeneration in AKI is not well understood and there is no effective clinical therapy that improves regeneration. The Notch signaling pathway plays an essential role in kidney development and has been implicated in tissue repair in the adult kidney. Here, we found that kidneys after experimental AKI in mice showed increased expression of Notch receptors, specifically Notch1-3, of the Notch ligands Jagged-1 (Jag1), Jag2 and Delta-like-4 (Dll4) and of the Notch target genes Hes1, Hey2, HeyL, Sox9 and platelet-derived growth factor receptor β (Pdgfrb). Treatment of ischemic mice with the γ-secretase inhibitor DBZ blocked Notch signaling and specifically downregulated the expression of Notch3 and the Notch target genes Hes1, Hey2, HeyL and Pdgfrb. After DBZ treatment, the mice developed less interstitial edema and displayed altered interstitial inflammation patterns. Furthermore, serum urea and creatinine levels were significantly decreased from 6 h onwards when compared to control mice treated with DMSO only. Our data are consistent with an amelioration of the severity of kidney injury by blocking Notch activation following AKI, and suggest an involvement of Notch-regulated Pdgfrb in AKI pathogenesis.

Keywords:
Acute kidney failure, Platelet-derived growth factor receptor β, Notch
1.
Angelotti, M.L., E. Ronconi, L. Ballerini, A. Peired, B. Mazzinghi, C. Sagrinati, E. Parente, M. Gacci, M. Carini, M. Rotondi, A.B. Fogo, E. Lazzeri, L. Lasagni, P. Romagnani (2012) Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury. Stem Cells 30: 1714-1725.
2.
Artavanis-Tsakonas, S., M.D. Rand, R.J. Lake (1999) Notch signaling: cell fate control and signal integration in development. Science 284: 770-776.
3.
Barak, H., K. Surendran, S.C. Boyle (2012) The role of Notch signaling in kidney development and disease. Adv Exp Med Biol 727: 99-113.
4.
Bielesz, B., Y. Sirin, H. Si, T. Niranjan, A. Gruenwald, S. Ahn, H. Kato, J. Pullman, M. Gessler, V.H. Haase, K. Susztak (2010) Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J Clin Invest 120: 4040-4054.
5.
Bonventre, J.V. (2003) Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol 14(suppl 1): S55-S61.
6.
Boyle, S.C., Z. Liu, R. Kopan (2014) Notch signaling is required for the formation of mesangial cells from a stromal mesenchyme precursor during kidney development. Development 141: 346-354.
7.
Cantley, L.G. (2005) Adult stem cells in the repair of the injured renal tubule. Nat Clin Pract Nephrol 1: 22-32.
8.
Cheng, H.T., M. Kim, M.T. Valerius, K. Surendran, K. Schuster-Gossler, A. Gossler, A.P. McMahon, R. Kopan (2007) Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 134: 801-811.
9.
Chen, J., J.K. Chen, E.M. Conway, R.C. Harris (2013) Survivin mediates renal proximal tubule recovery from AKI. J Am Soc Nephrol 24: 2023-2033.
10.
Chen, L., Q. Al-Awqati (2005) Segmental expression of Notch and Hairy genes in nephrogenesis. Am J Physiol Renal Physiol 288: F939-F952.
11.
Djudjaj, S., C. Chatziantoniou, U. Raffetseder, D. Guerrot, J.C. Dussaule, P. Boor, M. Kerroch, L. Hanssen, S. Brandt, A. Dittrich, T. Ostendorf, J. Floege, C. Zhu, M. Lindenmeyer, C.D. Cohen, P.R. Mertens (2012) Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury. J Pathol 228: 286-299.
12.
Fischer, A., M. Gessler (2007) Delta-Notch - and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 35: 4583-4596.
13.
Floege, J., F. Eitner, C.E. Alpers (2008) A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol 19: 12-23.
14.
Golde, T.E., E.H. Koo, K.M. Felsenstein, B.A. Osborne, L. Miele (2013) γ-Secretase inhibitors and modulators. Biochim Biophys Acta 1828: 2898-2907.
15.
Gupta, S., S. Li, M.J. Abedin, L. Wang, E. Schneider, B. Najafian, M. Rosenberg (2010) Effect of Notch activation on the regenerative response to acute renal failure. Am J Physiol Renal Physiol 298: F209-F215.
16.
Hoste, E.A., M. Schurgers (2008) Epidemiology of acute kidney injury: how big is the problem? Crit Care Med 36(4 suppl): S146-S151.
17.
Huang, R., Q. Zhou, P. Veeraragoo, H. Yu, Z. Xiao (2011) Notch2/Hes-1 pathway plays an important role in renal ischemia and reperfusion injury-associated inflammation and apoptosis and the γ-secretase inhibitor DAPT has a nephroprotective effect. Ren Fail 33: 207-216.
18.
Humphreys, B.D., M.T. Valerius, A. Kobayashi, J.W. Mugford, S. Soeung, J.S. Duffield, A.P. McMahon, J.V. Bonventre (2008) Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2: 284-291.
19.
Jin, S., E.M. Hansson, S. Tikka, F. Lanner, C. Sahlgren, F. Farnebo, M. Baumann, H. Kalimo, U. Lendahl (2008) Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ Res 102: 1483-1491.
20.
Kamath, B.M., G. Podkameni, A.L. Hutchinson, L.D. Leonard, J. Gerfen, I.D. Krantz, D.A. Piccoli, N.B. Spinner, K.M. Loomes, K. Meyers (2012) Renal anomalies in Alagille syndrome: a disease-defining feature. Am J Med Genet A 158A: 85-89.
21.
Kobayashi, T., Y. Terada, H. Kuwana, H. Tanaka, T. Okado, M. Kuwahara, S. Tohda, S. Sakano, S. Sasaki (2008) Expression and function of the Delta-1/Notch-2/Hes-1 pathway during experimental acute kidney injury. Kidney Int 73: 1240-1250.
22.
Kopan, R., M.X. Ilagan (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137: 216-233.
23.
Kusaba, T., M. Lalli, R. Kramann, A. Kobayashi, B.D. Humphreys (2014) Differentiated kidney epithelial cells repair injured proximal tubule. Proc Natl Acad Sci USA 111: 1527-1532.
24.
Li, L., I.D. Krantz, Y. Deng, A. Genin, A.B. Banta, C.C. Collins, M. Qi, B.J. Trask, W.L. Kuo, J. Cochran, T. Costa, M.E. Pierpont, E.B. Rand, D.A. Piccoli, L. Hood, N.B. Spinner (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16: 243-251.
25.
Liu, R., A. Trindade, Z. Sun, R. Kumar, F.A. Weaver, V. Krasnoperov, K. Naga, A. Duarte, P.S. Gill (2012) Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues. Biochem Biophys Res Commun 418: 173-179.
26.
Liu, Z., S. Chen, S. Boyle, Y. Zhu, A. Zhang, D.R. Piwnica-Worms, M.X. Ilagan, R. Kopan (2013) The extracellular domain of Notch2 increases its cell-surface abundance and ligand responsiveness during kidney development. Dev Cell 25: 585-598.
27.
Main, H., K.L. Lee, H. Yang, S. Haapa-Paananen, H. Edgren, S. Jin, C. Sahlgren, O. Kallioniemi, L. Poellinger, B. Lim, U. Lendahl (2010) Interactions between Notch- and hypoxia-induced transcriptomes in embryonic stem cells. Exp Cell Res 316: 1610-1624.
28.
McCright, B. (2003) Notch signaling in kidney development. Curr Opin Nephrol Hypertens 12: 5-10.
29.
McDaniell, R., D.M. Warthen, P.A. Sanchez-Lara, A. Pai, I.D. Krantz, D.A. Piccoli, N.B. Spinner (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am J Hum Genet 79: 169-173.
30.
Meier-Stiegen, F., R. Schwanbeck, K. Bernoth, S. Martini, T. Hieronymus, D. Ruau, M. Zenke, U. Just (2010) Activated Notch1 target genes during embryonic cell differentiation depend on the cellular context and include lineage determinants and inhibitors. PLoS One 5: e11481.
31.
Nakagawa, T., M. Sasahara, M. Haneda, H. Kataoka, H. Nakagawa, M. Yagi, R. Kikkawa, F. Hazama (1999) Role of PDGFβ-chain and PDGF receptors in rat tubular regeneration after acute injury. Am J Pathol 155: 1689-1699.
32.
Niranjan, T., B. Bielesz, A. Gruenwald, M.P. Ponda, J.B. Kopp, D.B. Thomas, K. Susztak (2008) The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 14: 290-298.
33.
Oda, T., A.G. Elkahloun, B.L. Pike, K. Okajima, I.D. Krantz, A. Genin, D.A. Piccoli, P.S. Meltzer, N.B. Spinner, F.S. Collins, S.C. Chandrasekharappa (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16: 235-242.
34.
Schwanbeck, R., S. Martini, K. Bernoth, U. Just (2011) The Notch signaling pathway: molecular basis of cell context dependency. Eur J Cell Biol 90: 572-581.
35.
Sirin, Y., K. Susztak (2012) Notch in the kidney: development and disease. J Pathol 226: 394-403.
36.
Sorensen-Zender, I., S. Rong, N. Susnik, S. Zender, P. Pennekamp, A. Melk, H. Haller, R. Schmitt (2014) Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury. Am J Physiol Renal Physiol 306: F907-F915.
37.
van Es, J.H., M.E. van Gijn, O. Riccio, M. van den Born, M. Vooijs, H. Begthel, M. Cozijnsen, S. Robine, D.J. Winton, F. Radtke, H. Clevers (2005) Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959-963.
© 2016 S. Karger AG, Basel
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.