Effect of Notch activation on the regenerative response to acute renal failure.
Episodes of acute renal failure (ARF) are not always fully reversible and may lead to chronic disease, due in part to an inadequate regenerative response. The Notch signaling pathway is involved in determining cell fate during development, and tissue maintenance and repair in adult organs. The purpose of this study was to examine the role of the Notch pathway in renal regeneration following ARF. Kidney injury, induced by ischemia-reperfusion, resulted in early activation of the Notch pathway, as evidenced by increased expression of Notch1 and Notch2 intracellular domain (cleaved Notch). The effect of exogenous administration of the Notch ligand Delta-like-4 (DLL4) on recovery from ARF was then studied. Rats were pretreated by intraperitoneal injection of DLL4 or vehicle control. Two days following the last DLL4 dose, ARF was induced by bilateral renal artery clamping for 45 min followed by reperfusion. The severity of renal injury was similar in DLL4 and control rats. Renal recovery was facilitated by DLL4 treatment, as evidenced by faster return of serum creatinine to baseline by 48 h in DLL4-treated rats as against 5 days in vehicle-treated control rats. Cell proliferation was higher in the DLL4-treated group. In conclusion, activation of the Notch pathway occurs following ARF. Pretreatment with the Notch ligand DLL4 enhanced recovery from ARF and represents a potential novel therapeutic option for regenerating the injured kidney.
Gupta
Sandeep
S
Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota 55414, USA.
Li
Shunan
S
Abedin
Md J
MJ
Wang
Lawrence
L
Schneider
Eric
E
Najafian
Behzad
B
Rosenberg
Mark
M
D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000473:pathology / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000502:physiology*; D051883:Receptor, Notch2 / Q000502:physiology*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D015427:Reperfusion Injury / Q000150:complications; D015398:Signal Transduction / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497763:Notch1 protein, rat; C497766:Notch2 protein, rat; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C064045:delta protein