Notch receptors and their canonical
ligands are transmembrane
proteins of the
EGF-like family, expressed in the cell surface.
Notch receptors are synthesized as single
peptides and undergo three sequential proteolytic cleavage steps before rendering an active
transcription factor, the Notch intracellular domain (NICD).
Ligand binding facilitates release of NICD by γ-
secretase. Evidence for the role of the Notch pathway in kidney injury comes from studies on activation of Notch by canonical
ligands in cultured cells, on inhibition/targeting of γ-
secretase in culture or in vivo, on genetic deletion of common Notch pathway
proteins such as CSL, or descriptions of increased transcription of Notch target genes in kidney injury. Inhibitors of γ-
secretase prevent
fibrosis in experimental kidney injury. However, these drugs may modulate other signalling systems beyond Notch and are toxic in human trials. Information regarding the specific contribution of each receptor to kidney injury may help design better targeted therapeutic approaches. In this regard, overexpression of NICD1, NCID2, NICD3 or NICD4 elicits
biological responses in cultured renal cells that include cell proliferation, apoptosis, and inflammatory and profibrotic responses, depending on the particular NICD. Furthermore, immunostaining for NICD1, NICD2, and NICD4 suggestive of receptor activation has been observed in glomerular and tubular cells in human and experimental
kidney disease. Delayed conditional Notch1 or Notch2 inactivation facilitates
cyst formation, and NICD1 overexpression in podocytes or tubular cells promotes glomerulosclerosis and interstitial
fibrosis. Kidney injury is a feature of human Notch2 mutations and
CADASIL patients with mutated Notch3 may display renal injury. Notch3-/- mice display increased sensitivity to
angiotensin II-induced kidney injury but are less sensitive to tubular injury,
inflammation, and
fibrosis following unilateral
ureteral obstruction. The recent availability of
blocking antibodies specific for Notch1, Notch2, and Notch3 may help to elucidate the therapeutic potential of specific targeting of individual
Notch receptors in
kidney disease.