Notch3 and kidney injury: never two without three

Abstract

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.