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

@article{SrensenZender2014RenalTN,
  title={Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury.},
  author={Inga S{\"o}rensen-Zender and Song Rong and Nathan Susnik and Steffen Zender and Petra Pennekamp and Anette Melk and Hermann Haller and Roland Schmitt},
  journal={American journal of physiology. Renal physiology},
  year={2014},
  volume={306 8},
  pages={
          F907-15
        }
}
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… 
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References

SHOWING 1-10 OF 47 REFERENCES

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.

It is established that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.

Effect of Notch activation on the regenerative response to acute renal failure.

Pretreatment with the Notch ligand DLL4 enhanced recovery from ARF and represents a potential novel therapeutic option for regenerating the injured kidney.

Notch‐3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury

Notch‐3 receptor fulfils non‐redundant roles in the inflamed kidney that may not be replaced by other Notch receptor family members, and specific blockade of this receptor may be suitable as therapeutic option to delay progression of kidney disease.

Expression and function of the Delta-1/Notch-2/Hes-1 pathway during experimental acute kidney injury.

This study suggests that the Delta-1/Notch-2/Hes-1 signaling pathway may regulate the regeneration and proliferation of renal tubules during acute kidney injury.

The Notch pathway in podocytes plays a role in the development of glomerular disease

Observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.

Survivin mediates renal proximal tubule recovery from AKI.

Data suggest that STAT3 phosphorylation and subsequent upregulation of survivin expression mediated by Notch-2 signaling in renal proximal tubule epithelial cells aid in the functional and structural recovery of the kidney from AKI.

Increased Cellular Senescence and Vascular Rarefaction Exacerbate the Progression of Kidney Fibrosis in Aged Mice Following Transient Ischemic Injury

Longer acute injury in the aged animals results in an accelerated progression of kidney disease in a chronic state, demonstrating that age exacerbates the fibrosis and inflammation that develop in the sequelae of progressive kidney disease following acute injury.

Notch2/Hes-1 Pathway Plays an Important Role in Renal Ischemia and Reperfusion Injury-Associated Inflammation and Apoptosis and the γ-Secretase Inhibitor DAPT has a Nephroprotective Effect

I/R activates Notch2/hes-1 signaling and DAPT treatment can ameliorate the severity of tubular damage after renal IRI, lower the expression of NF-κB2, MCP-1, and bax protein, increase the expressionof bcl-2 protein, and reduce the ratio of terminal 2-deoxyuridine 5-triphosphate nick end-labeling-positive cells.

Zag expression during aging suppresses proliferation after kidney injury.

It is demonstrated that increased Zag expression in the aged kidney acts to suppress the proliferative response to injury and introduce Zag as a modifier of the aging phenotype.

Cellular senescence limits regenerative capacity and allograft survival.

Lost INK4a locus in mice is associated with improved renal function, conservation of nephron mass, and transplant survival and a pathogenic role of renal cellular senescence in the development of interstitial fibrosis and tubular atrophy and kidney graft deterioration by preventing the recovery from injury is suggested.