Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury

Am J Physiol Renal Physiol. 2014 Apr 15;306(8):F907-15. doi: 10.1152/ajprenal.00030.2014. Epub 2014 Feb 26.


The aging kidney has a diminished regenerative potential and an increased tendency to develop tubular atrophy and fibrosis after acute injury. In this study, we found that activation of tubular epithelial Notch1 signaling was prolonged in the aging kidney after ischemia/reperfusion (IR) damage. To analyze the consequences of sustained Notch activation, we generated mice with conditional inducible expression of Notch1 intracellular domain (NICD) in proximal tubules. NICD kidneys were analyzed 1 and 4 wk after renal IR. Conditional NICD expression was associated with aggravated tubular damage, a fibrotic phenotype, and the expression of cellular senescence markers p21 and p16(INK4a). In wild-type mice pharmacological inhibition of Notch using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) improved tubulo-interstitial damage and antagonized the prosenescent pathway activation after IR. In vitro, activation of Notch signaling with delta-like-ligand-4 caused prosenescent changes in tubular cells while inhibition with DAPT attenuated these changes. In conclusion, our data suggest that sustained epithelial Notch activation after IR might contribute to the inferior outcome of old kidneys after injury. Sustained epithelial activation of Notch is associated with a prosenescent phenotype and maladaptive repair.

Keywords: acute kidney injury; cellular senescence; notch signaling; renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / physiopathology*
  • Adaptor Proteins, Signal Transducing
  • Aging
  • Animals
  • Calcium-Binding Proteins
  • Cellular Senescence / drug effects
  • Dipeptides / pharmacology
  • Fibrosis
  • Intracellular Signaling Peptides and Proteins / pharmacology
  • Kidney Tubules / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Male
  • Membrane Proteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Receptor, Notch1 / biosynthesis
  • Receptor, Notch1 / physiology*
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology


  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Dipeptides
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Receptor, Notch1