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Review
. 2012 Jan;226(2):394-403.
doi: 10.1002/path.2967. Epub 2011 Aug 24.

Notch in the kidney: development and disease

Yasemin Sirin  1 , Katalin Susztak
Affiliations
Review

Notch in the kidney: development and disease

Yasemin Sirin et al. J Pathol. 2012 Jan.

Abstract

Notch signalling is a highly conserved cell-cell communication mechanism that regulates development, tissue homeostasis, and repair. Within the kidney, Notch has an important function in orchestrating kidney development. Recent studies indicate that Notch plays a key role in establishing proximal epithelial fate during nephron segmentation as well as the differentiation of principal cells in the renal collecting system. Notch signalling is markedly reduced in the adult kidney; however, increased Notch signalling has been noted in both acute and chronic kidney injury. Increased glomerular epithelial Notch signalling has been associated with albuminuria and glomerulosclerosis, while tubular epithelial Notch activation caused fibrosis development most likely inducing an improper epithelial repair pathway. Recent studies thereby indicate that Notch is a key regulator of kidney development, repair, and injury.

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Conflict of interest statement

There is no conflict of interest.

Figures

Figure 1
Figure 1. Canonical Notch signalling
The signal-sending cell presents the ligand, belonging to the DSL (Delta, Serrate, Lag-2) family to the signal-receiving cell, expressing a Notch receptor on its cell surface. This leads to a sequential cleavage of Notch through ADAM metalloproteinases at site S2 and the ɣ-secretase complex at site S3. The released extracellular domain of Notch is endocytosed along with the ligand, whereas the cleaved intracellular Notch (NICD) translocates to the nucleus where it interacts with its binding partner Rbpj, thus driving target gene (for example Hes, Hey) transcription.
Figure 2
Figure 2. Notch plays role in proximal tubule specification and establishing the cell composition of the collecting duct
The renal epithelium is formed by reciprocally inductive interactions between two different mesenchymal precursor tissues; the ureteric bud (UB) and the metanephric mesenchyme (MM). Sine oculis homeobox domain 2 (SIX2) suppreses tubulogenesis in the mesenchyme. Glial cell line-derived neurotrophic factor is secreted by the MM attracts the UB toward the mesenchyme. The UB secretes Wnt9b and induces the mesenchyme to epithelial (MET) condensation via inducing Fgf8, Lhx1 and Wnt4. After MET, the nascent epithelial renal vesicles (RV) form a proximo-distal axis, where the surface facing the cortex is distal (yellow) and the medullary surface is proximal (green). The proximal segment of the S-shaped body is thought to give rise to the future glomerulus and proximal tubule, Wt1 and Notch2 plays key role in defining these segments. Endothelial cells are attracted by vascular endothelial growth factor (VEGF) and platalet derived growth factorβ (PDGFβ). (D) The mature nephron is further subdivided to glomerulus (green), proximal tubule (red), the the loop of Henle (orange), distal convoluted tubule (yellow), which connects to the collecting duct (blue). The scheme adapted and modified from Schedl et al (34).
Figure 3
Figure 3. Expression of Notch1 in healthy and diseased human kidney
Representative immunostaining images showing cleaved Notch1 stainings on control and chronic kidney diseased (CKD) human kidneys. Scale bars: 50 μm
Figure 4
Figure 4. Increased expression of Notch in kidney induces fibrosis development
A. In the adult kidney very few tubular epithelial cells expression Notch1 and Jagged1. In injury expression of Notch1 and Jagged1 is increased. Notch activation induces proliferationa and failed differentiation of tubular epithelial cells. In addition, epithelial Notch activation induces fibroblast proliferation and myofibroblast activation. B. Representative histological images of control mouse kidneys and from mice with tubule specific Notch1 expression (Pax8rtTA/TREICNotch1).
Figure 4
Figure 4. Increased expression of Notch in kidney induces fibrosis development
A. In the adult kidney very few tubular epithelial cells expression Notch1 and Jagged1. In injury expression of Notch1 and Jagged1 is increased. Notch activation induces proliferationa and failed differentiation of tubular epithelial cells. In addition, epithelial Notch activation induces fibroblast proliferation and myofibroblast activation. B. Representative histological images of control mouse kidneys and from mice with tubule specific Notch1 expression (Pax8rtTA/TREICNotch1).
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References

    1. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–776. - PubMed
    1. Sharma S, Sirin Y, Susztak K. The story of Notch and chronic kidney disease. Curr Opin Nephrol Hypertens. 20:56–61. - PMC - PubMed
    1. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–233. - PMC - PubMed
    1. Ilagan MX, Kopan R. SnapShot: notch signaling pathway. Cell. 2007;128:1246. - PubMed
    1. Shi S, Stanley P. Protein O-fucosyltransferase 1 is an essential component of Notch signalingpathways. Proc Natl Acad Sci U S A. 2003;100:5234–5239. - PMC - PubMed

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