Skip Navigation


NDT Advance Access originally published online on May 25, 2008
Nephrology Dialysis Transplantation 2008 23(9):2743-2745; doi:10.1093/ndt/gfn279
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/9/2743    most recent
gfn279v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Mertens, P. R.
Right arrow Articles by Rauen, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mertens, P. R.
Right arrow Articles by Rauen, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Notch receptors: a new target in glomerular diseases*

Peter R. Mertens, Ute Raffetseder and Thomas Rauen

Division of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Germany

Correspondence and offprint requests to: Peter R. Mertens, Division of Nephrology and Clinical Immunology, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. Tel: +49-241-8089756; Fax: +49-241-8082446; E-mail: Pmertens{at}ukaachen.de

Keywords: diabetic nephropathy; glomerulonephritis; Notch; podocyte; TGF-β

In 1919 the geneticist Thomas Morgan was the first to describe notched wings in fruit flies and in 1985 a novel class of single trans-membrane receptors relating to this intriguing phenotype was cloned [1]. Since then, the interest in these receptors involved in cell–cell communication has spilled over into multiple clinical disciplines and has paved the way to novel insights, ranging from Alzheimer's disease [2] and CADASIL syndrome [3] to cancer [4]. Specific inhibitors that selectively target the activation of the Notch-signalling pathway are now available and enter the stage of clinical trials. These components bear also great potential for the treatment of renal diseases, given that experimental data link this signalling pathway to diverse glomerular diseases.

The Notch receptor family includes four members in mammalians that are all anchored in the cell membranes as heterodimers and are involved in short-range cell–cell communication, cell-fate decision, patterning and cell polarity [5]. Classical Notch ligands, e.g. those of the Serrate or Delta family, also contain a transmembrane domain and are anchored in the cell membranes. Receptor occupation by ligands promotes two proteolytic changes of the receptor protein, exerted by an ADAM metalloprotease [6] and a {gamma}-secretase [7], the latter belonging to the presenilin family. Proteolytic cleavage of the receptor releases the intracellular domains, which are targeted to the cell nucleus and associate with other transcriptional regulators, most importantly Rbpj. As a result, the gene transcription of a family of transcription factors belonging to the hairy enhancer of split (HES) and Hey family is altered [8] (see Figure 1).


Figure 1
View larger version (30K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 (A) Schematic diagram of the Notch receptor domains. Notch receptors are composed of extracellular domains containing epidermal growth factor (EGF)-like repeats and a Lin-12 repeat, a short transmembrane (TM) region and intracellular domains (RAM: Rbpj interacting domain; NLS: nuclear localization signal; TAD: transactivation domain; PEST: region rich in proline, glutamine, serine and threonine). Proteolytic cleavage sites are indicated as S1, S2 and S3. (B) Key steps in receptor Notch activation and signalling. Upon ligand (e.g Delta and Serrate) binding (1) two consecutive proteolytic steps (S2, S3) within the Notch receptor mediate its dissociation (2) and subsequent translocation of intracellular domains to the nucleus (3). Here, it associates with Rbpj and forms a transcriptional regulator complex (4) that activates target genes, including HES and Hey.

 


   Summary of key findings
Top
 Summary of key findings
Background
 Take-home messages
 References
 
In the March issue of Nature Medicine, Niranjan et al. provide novel insights into the role of the Notch receptor family into the onset of sclerosing glomerular disease [9]. Members of this protein family are expressed in mature podocytes of humans and rodents with diabetic nephropathy and focal segmental sclerosis.

In two experimental models for diabetic nephropathy, Lprdb/db mice mimicking type II diabetes and streptozotocin-treated mice recapitulating type I diabetes, the authors detected activated Notch-1 and -2 signalling, which was absent in mature kidneys of healthy control animals. Similarly, in a model of podocyte-damage induced by puromycin aminonucleoside (PAN), a largely podocyte-restricted activation of Notch-1 was apparent. Analogous findings were made in patients suffering from diabetic nephropathy or FSGS.

Elegant studies using transgenic mice that constitutively express the active intracellular domains of Notch-1 were set up, demonstrating the onset of proteinuria within 5 days following gene induction, accompanied by mesangial expansion with ensuing segmental glomerulosclerosis and tubulointerstitial fibrosis. Underlying alterations included massive podocyte loss by apoptosis due to caspase activation and foot-process effacement. The authors next focused their attention on TGF-β, a recognized mediator of renal injury and an activator of Notch signalling. TGF-β increased Notch-1 receptor and Notch ligand Jagged1 expression. Pharmacologic inhibition of the Notch processing by {gamma}-secretase inhibitors (GSI) prevented Notch upregulation, whereas ligand expression was unaltered. Signalling events upregulated by Notch activation included p53 and Cdkn1a (p21), which were involved in cell apoptosis.

The study proceeded with mice that harbour a podocyte-specific deletion of the Rbpj gene in mature glomeruli. These animals exhibited no histomorphologic abnormalities, indicating that Notch signaling via Rbpj in podocytes is dispensable for mature glomeruli integrity. Strepozotocin application resulted in substantial albuminuria within 20 weeks in control animals whereas animals with Rbpj deletion were partially protected from damage and exhibited 50% lower albuminuria levels, more WT1-positive podocytes with unimpaired nephrin and podocin expression and lower levels of TGF-β and VEGF. Finally, the aforementioned PAN model was set up in non-transgenic mice with concomitant GSI application. Even 4 days after PAN application GSI successfully protected podocytes from toxic sequelae, restored foot-process effacement and prevented proteinuria.



   Background
Top
 Summary of key findings
 Background
Take-home messages
 References
 
The Notch pathway is indispensable for glomerular development. Nephrons without glomeruli and proximal tubules are observed in animal models with absent receptor Notch-1 or depleted enzymes presenilins 1 and 2 [10]. Ectopic Notch activation in developing podocytes on the other hand causes glomerulosclerosis in developing murine kidneys and opposes terminal differentiation of podocytes [11].

Zavadil et al. [12] previously described an interaction of TGF-β and Notch signalling in keratinocytes. This interaction seems to form a positive feedback loop: TGF-β transcriptionally upregulates Notch ligand Jagged1 expression. On the other hand, Notch-1 signalling upregulated TGF-β expression. Given the potent profibrotic activity of TGF-β in glomerular disease, Notch signalling may be a culprit to damage onset and perpetuation. The findings by Niranjan et al. [9] also delineate that Notch signalling plays a non-redundant role for the fate of podocytes to survive or undergo apoptosis. In this regard podocytes resemble other terminally differentiated cells, keratinocytes and neurons [13,14].

A recent publication by Teachey et al. indicated that GSI are able to prevent disease activity in experimental models of autoimmune and lymphoproliferative diseases [15]. Inhibition of Notch signalling reduced T-cell proliferation as well as synthesis of autoantibodies and effectively ameliorated lupus nephritis.

Notably, researchers in the cancer field propose that the withdrawal of Notch signalling induces a state of hibernation, a state that may be also protective for podocytes under profound stress. GSI compounds have entered Phase 2 and 3 clinical trials for the treatment of diverse diseases, ranging from Alzheimer's disease to leukaemia [16,17]. Should these studies reveal efficacy without considerable side effects, they bear the potential to be included into the armoury of nephrologists to combat renal diseases as well.



   Take-home messages
Top
 Summary of key findings
 Background
 Take-home messages
References
 
Two potent mediators of cell communication and fibrogenesis are intertwined, Notch and TGF-β signalling. Despite the complexity of the Notch receptor family and its associated ligands, the findings by Niranjan et al. [9] open the prospect that pharmacologic inhibition of this signalling pathway may prevent and even reverse damage to the glomeruli. Life and death decisions are made by this pathway in podocytes under stress. The study also reiterates the fundamental role that podocytes play in diverse glomerular diseases, such as diabetic nephropathy and focal segmental glomerulosclerosis.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Niranjan T, Bielesz B, Gruenwald A et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 2008; 14: 290–298. Back



   References
Top
 Summary of key findings
 Background
 Take-home messages
 References
 

  1. Grimwade BG, Muskavitch MA, Welshons WJ, et al. The molecular genetics of the Notch locus in drosophila melanogaster. Dev Biol (1985) 107:503–519.[CrossRef][Web of Science][Medline]
  2. Wolfe MS. Therapeutic strategies for Alzheimer's disease. Nat Rev Drug Discov (2002) 1:859–866.[CrossRef][Web of Science][Medline]
  3. Joutel A, Corpechot C, Ducros A, et al. Notch 3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature (1996) 383:707–710.[CrossRef][Web of Science][Medline]
  4. van Es JH, van Gijn ME, Riccio O, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature (2005) 435:959–963.[CrossRef][Web of Science][Medline]
  5. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol (2006) 7:678–689.[CrossRef][Web of Science][Medline]
  6. Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell (2000) 5:207–216.[CrossRef][Web of Science][Medline]
  7. Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature (1998) 393:382–386.[CrossRef][Web of Science][Medline]
  8. Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol (2003) 194:237–255.[CrossRef][Web of Science][Medline]
  9. Niranjan T, Bielesz B, Gruenwald A, et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med (2008) 14:290–298.[CrossRef][Web of Science][Medline]
  10. Cheng HT, Kopan R. The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int (2005) 68:1951–1952.[CrossRef][Web of Science][Medline]
  11. Waters AM, Wu MY, Onay T, et al. Ectopic Notch activation in developing podocytes causes glomerulosclerosis. J Am Soc Nephrol (2008) in press.
  12. Zavadil J, Cermak L, Soto-Nieves N, et al. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. Embo J (2004) 23:1155–1165.[CrossRef][Web of Science][Medline]
  13. Rangarajan A, Talora C, Okuyama R, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. Embo J (2001) 20:3427–3436.[CrossRef][Web of Science][Medline]
  14. Zavadil J, Bitzer M, Liang D, et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA (2001) 98:6686–6691.[Abstract/Free Full Text]
  15. Teachey DT, Seif AE, Brown VI, et al. Targeting Notch signaling in autoimmune and lymphoproliferative disease. Blood (2008) 111:705–714.[Abstract/Free Full Text]
  16. Garber K. Notch emerges as new cancer drug target. J Natl Cancer Inst (2007) 99:1284–1285.[Free Full Text]
  17. Siemers ER, Quinn JF, Kaye J, et al. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology (2006) 66:602–604.[Abstract/Free Full Text]
Received for publication: 14. 4.08
Accepted in revised form: 22. 4.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 DevelopmentHome page
R. W. Naylor and E. A. Jones
Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros
Development, November 1, 2009; 136(21): 3585 - 3595.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Rauen, U. Raffetseder, B. C. Frye, S. Djudjaj, P. J. T. Muhlenberg, F. Eitner, U. Lendahl, J. Bernhagen, S. Dooley, and P. R. Mertens
YB-1 Acts as a Ligand for Notch-3 Receptors and Modulates Receptor Activation
J. Biol. Chem., September 25, 2009; 284(39): 26928 - 26940.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/9/2743    most recent
gfn279v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Mertens, P. R.
Right arrow Articles by Rauen, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mertens, P. R.
Right arrow Articles by Rauen, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?