Notch Signaling Pathways in Kidney Pathophysiology
Summary
The Notch signalling network is a highly conserved cell–cell communication system that regulates cell fate, proliferation and differentiation throughout development and into adult tissue homeostasis. In the kidney, Notch receptors (Notch1–4) and their ligands (Jagged and Delta-like families) are dynamically expressed in glomerular and tubular compartments. During nephrogenesis, Notch activity guides nephron segmentation and podocyte maturation; in the mature organ, low basal signalling contributes to tubular repair following injury. Dysregulation of Notch drives maladaptive responses in chronic kidney disease, promoting epithelial–mesenchymal transition, interstitial myofibroblast activation and extracellular matrix deposition that culminate in fibrosis. Pathogenic Notch activation also perturbs cellular metabolism, notably via suppression of mitochondrial transcription factor A, and engages pro-inflammatory cascades through cross-talk with TGF-β and STAT pathways. Conversely, targeted inhibition of specific receptor–ligand pairs has been shown to attenuate fibrogenic programmes and preserve renal architecture in experimental models. The global health burden of chronic and diabetic nephropathies underscores the importance of deciphering ligand–receptor specificity, downstream transcriptional networks and cell-type-specific roles of Notch isoforms. Emerging work seeks to exploit pathway modulators or receptor-selective antagonists to arrest progression of kidney injury and restore regenerative potential without compromising essential repair mechanisms.
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Notch Signaling Pathways in Kidney Pathophysiology publication trend
The graph below shows the total number of articles in notch signaling pathways in kidney pathophysiology across all publications each year (not limited to Nature Index journals).
Technical terms
Notch signalling pathway: A cell–cell communication cascade involving transmembrane receptors and ligands that regulates gene transcription following proteolytic release of the Notch intracellular domain.
Epithelial–mesenchymal transition (EMT): A process in which epithelial cells lose polarity and adhesion, acquiring a motile, fibroblast-like phenotype associated with fibrosis.
Myofibroblast: An activated mesenchymal cell expressing contractile proteins and producing extracellular matrix, central to tissue scarring.
Renal fibrosis: Pathological accumulation of extracellular matrix in the kidney interstitium, leading to organ stiffening and functional decline.
FSP-1-positive cell: A population of fibroblast-specific protein 1–expressing cells, including inflammatory monocytes, implicated in fibrotic responses.
Tubular epithelial cell (TEC): A specialised cell lining the nephron tubules, responsible for solute and water reabsorption and capable of regenerative responses.
Tfam: Mitochondrial transcription factor A, essential for mitochondrial DNA maintenance and energy metabolism, directly regulated by Notch in tubular cells.
References
- Notch Blockade Specifically in Bone Marrow-Derived FSP-1-Positive Cells Ameliorates Renal Fibrosis. Cells (2023).
- Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. PLOS Biology (2018).
- Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis. Cell Communication and Signaling (2019).
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